High-dose vitamin C improves norepinephrine level in patients with septic shock: A single-center, prospective, randomized controlled trial.

BACKGROUND: The effects of vitamin C supplementation on patients with septic shock remain controversial. We aimed to evaluate the effects of different vitamin C dosages on norepinephrine (NE) synthesis in adult patients with septic shock. METHODS: A total of 58 patients with septic shock admitted to our intensive care unit (ICU) between July 2021 and December 2022 were included. Patients were randomly divided into 3 groups: high-dose vitamin C (150 mg/kg/d, group A), low-dose vitamin C (50 mg/kg/d, group B), and placebo (group C). NE synthesis-related indicators (dopamine-ß-hydroxylase [DßH], tyrosine hydroxylase [TH], tetrahydrobiopterin [BH4], and dopamine [DA]), plasma NE, and vitamin C levels were measured every 24 hours and analyzed. All-cause mortality within 28 days and other clinical outcomes (including Acute Physiology and Chronic Health Evaluation [APACHE], Sequential Organ Failure Assessment [SOFA], and Multiple-Organ Dysfunction Syndrome [MODS] scores) were compared. RESULTS: Changes in TH, BH4, and DßH levels at 96 hours in groups A and B were greater than those in group C. These differences became more pronounced over the course of the intravenous vitamin C administration. Significant differences between groups A and C were detected at 96-hours TH, 72-hours BH4, 96-hours BH4, 96-hours DA, and DßH levels every 24 hours. The 96-hours TH, 96-hours BH4, and 48-hours DßH in group B were significantly higher than those in group C. The NE levels every 24 hours in groups A and B were higher than those in group C, group A and group C had a statistically significant difference. The 96-hours exogenous NE dosage in groups A and B was significantly lower than that in group C. No significant reductions in APACHE, SOFA, or MODS scores were observed in the vitamin C group, including the duration of ICU stay and mechanical ventilation. The 28-days mortality was lower in groups A and B than in group C (0%, 10%, and 16.67%, P = .187), but the difference was not significant. CONCLUSION: For patients with septic shock, treatment with vitamin C significantly increased TH, BH4, and DßH levels and reduced the exogenous NE dosage, but did not significantly improve clinical outcomes.

Photochemical evolution of the molecular composition of dissolved organic carbon and dissolved brown carbon from wood smoldering.

Recently, extreme wildfires occur frequently around the world and emit substantial brown carbon (BrC) into the atmosphere, whereas the molecular compositions and photochemical evolution of BrC remain poorly understood. In this work, primary smoke aerosols were generated from wood smoldering, and secondary smoke aerosols were formed by the OH radical photooxidation in an oxidation flow reactor, where both primary and secondary smoke samples were collected on filters. After solvent extraction of filter samples, the molecular composition of dissolved organic carbon (DOC) was determined by Fourier transform ion cyclotron resonance mass spectrometry (FTICR MS). The molecular composition of dissolved BrC was obtained based on the constraints of DOC formulae. The proportion of dissolved BrC fractions accounted for approximately 1/3-1/2 molecular formulae of DOC. The molecular characteristics of dissolved BrC showed higher levels of carbon oxidation state, double bond equivalents, and modified aromaticity index than those of DOC, indicating that dissolved BrC fractions were a class of organic structures with relatively higher oxidation state, unsaturated and aromatic degree in DOC fractions. The comparative analysis suggested that aliphatic and olefinic structures dominated DOC fractions (contributing to 70.1%-76.9%), while olefinic, aromatic, and condensed aromatic structures dominated dissolved BrC fractions (contributing to 97.5%-99.9%). It is worth noting that dissolved BrC fractions only contained carboxylic-rich alicyclic molecules (CRAMs)-like structures, unsaturated hydrocarbons, aromatic structures, and highly oxygenated compounds. CRAMs-like structures were the most abundant species in both DOC and dissolved BrC fractions. Nevertheless, the specific molecular characteristics for DOC and dissolved BrC fractions varied with subgroups after aging. The results highlight the similarities and differences in the molecular compositions and characteristics of DOC and dissolved BrC fractions with aging. This work will provide insights into understanding the molecular composition of DOC and dissolved BrC in smoke.

Activation of peroxymonosulfate with natural pyrite-biochar composite for sulfamethoxazole degradation in soil: Organic matter effects and free radical conversion.

Peroxymonosulfate (PMS)-based advanced oxidation processes (AOPs) represent an effective method for the remediation of antibiotic-contaminated soils. In this study, a natural pyrite-biochar composite material (FBCx) was developed, demonstrating superior activation performance and achieving a 76% removal rate of SMX from soil within 120 min. There existed different degradation mechanisms for SMX in aqueous and soil solutions, respectively. The production of 1O2 and inherent active species produced by soil slurry played an important role in the degradation process. The combination of electron paramagnetic resonance (EPR) and free radical probe experiments confirmed the presence of free radical transformation processes in soil. Wherein, the·OH and SO4·- generated in soil slurry did not directly involve in the degradation process, but rather preferentially reacted with soil organic matter (SOM) to form alkyl-like radicals (R·), thereby maintaining a high concentration of reactive species in the system. Furthermore, germination and growth promotion of mung bean seeds observed in the toxicity test indicated the environmental compatibility of this remediation method. This study revealed the influence mechanism of SOM in the remediation process of contaminated soil comprehensively, which possessed enormous potential for application in practical environments.

Photo-Reactivity of dissolved black carbon unveiled by combination of optical spectroscopy and FT-ICR MS analysis: Effects of pyrolysis temperature.

Dissolved black carbon (DBC) has high photoactivity, which plays an important role in contaminants photodegradation. However, it is unclear how pyrolysis temperatures would affect the composition and photo-reactivity of DBC at the molecular level. Herein, we combined complementary techniques to study the characteristics of DBC pyrolyzed at 200 - 500 ℃, as well as the photoproduction of reactive species and the photodegradation of tetracycline (TC). Bulk composition characterization found that condensed aromatic carbonyl compounds (ConAC) with narrow molecular weights in DBC experienced an increase from 200 to 500 °C, which enhanced the photoproduction of 3DBC*,1O2, and ·OH. Molecular-level data suggested that 3DBC* and 1O2 were both related to the same DBC compounds. Comparatively, the patterns for ·OH were less pronounced, implying its precursor was not 3DBC* and had more complexity. Plentiful CHOx species of ConAC in DBC400 and DBC500 (DBCT, where T = pyrolysis temperature) accelerated the generation of 3DBC* and 1O2, enhancing the photodegradation of TC, and mainly triplet states of quinones reacted with TC. In contrast, DBC200 and DBC300 exhibited inhibition since massive CHOx species in lignin-like reduced 3TC* to TC. Our data revealed the diverse photochemical behavior mechanisms of DBC pyrolyzed at 200 - 500 ℃ at the molecular level and the implications for aquatic contaminants photochemistry.

Treatment of multiple myeloma with selinexor: a review.

Over the last 20 years, breakthroughs in accessible therapies for the treatment of multiple myeloma (MM) have been made. Nevertheless, patients with MM resistant to immunomodulatory drugs, proteasome inhibitors, and anti-CD38 monoclonal antibodies have a very poor outcome. Therefore, it is necessary to explore new drugs for the treatment of MM. This review summarizes the mechanism of action of selinexor, relevant primary clinical trials, and recent developments in both patients with relapsed/refractory myeloma and patients with newly diagnosed myeloma. Selinexor may be useful for the treatment of refractory MM.

The Potential and Challenges of Selinexor in the Treatment of Multiple Myeloma Multiple myeloma (MM) is a plasma-cell neoplasm that presents with a variety of clinical manifestations, including bone destruction, anemia, renal dysfunction, and hypercalcemia, which pose a serious threat to people's health. Over the past 20 years, the survival of MM patients has significantly improved thanks to the development of several new treatments. However, the disease remains incurable, and almost all patients eventually develop a disease that is ineffective against available treatments. Therefore, an important area of research is the discovery of drugs with novel mechanisms of action to overcome the resistance mechanisms of current drugs. Selinexor is an oral XPO1 inhibitor that exerts anti-tumor activity through a novel mechanism. Here, we review the current clinical trials evaluating its role in the treatment of multiple myeloma and have a discussion of its mechanism, adverse events, challenges, and limitations. Selinexor is a promising drug. It may be a good addition to the treatment of relapsed and refractory multiple myeloma, but more research is needed to unlock its further potential.

OsWRKY76 positively regulates drought stress via OsbHLH148-mediated jasmonate signaling in rice.

Drought stress is a major environmental threat that limits plant growth and crop productivity. Therefore, it is necessary to uncover the molecular mechanisms behind drought tolerance in crops. Here, OsWRKY76 positively regulated drought stress in rice. OsWRKY76 expression was induced by PEG treatment, dehydration stress, and exogenous MeJA rather than by no treatment. Notably, OsWRKY76 knockout weakened drought tolerance at the seedling stage and decreased MeJA sensitivity. OsJAZ12 was significantly induced by drought stress, and its expression was significantly higher in OsWRKY76-knockout mutants than in wild-type ZH11 under drought stress. Yeast two-hybrid and bimolecular fluorescence complementation assays showed that OsWRKY76 interacted with OsJAZ12. OsWRKY76 weakened the interaction between OsbHLH148 and OsJAZ12 in yeast cells. The OsJAZ12 protein repressed the transactivation activity of OsbHLH148, and this repression was partly restored by OsWRKY76 in rice protoplasts. Moreover, OsDREB1E expression was lower in OsWRKY76-knockout mutants than in wild-type ZH11 under drought stress, but it was upregulated under normal growth conditions. Yeast one-hybrid, electrophoretic mobility shift, and dual-luciferase assays showed that OsWRKY76 and OsbHLH148 bound directly to the OsDREB1E promoter and activated OsDREB1E expression in response to drought stress. These results suggest that OsWRKY76 confers drought tolerance through OsbHLH148-mediated jasmonate signaling in rice, offering a new clue to uncover the mechanisms behind drought tolerance.

Elevated levels of interleukin-33 are associated with asthma: A meta-analysis.

BACKGROUND: Previous studies reported that patients with asthma showed higher levels of interleukin (IL)-33 in peripheral blood, compared to healthy control (HCs). However, we also noticed that there were no significant differences of IL-33 levels between controls and asthma patients in a recent study. We aim to conduct this meta-analysis and evaluate the feasibility of IL-33 in peripheral blood that may act as a promising biomarker in asthma. METHODS: Articles published before December 2022 were searched in these databases (PubMed, Web of Science, EMBASE, and Google Scholar). We used STATA 12.0 software to compute the results. RESULTS: The study showed that asthmatics showed higher IL-33 level in serum and plasma, compared to HCs (serum: standard mean difference [SMD] 2.06, 95% confidence interval [CI] 1.12-3.00, I2 = 98.4%, p < .001; plasma: SMD 3.67, 95% CI 2.32-5.03, I2 = 86.0%, p < .001). Subgroup analysis indicated that asthma adults showed higher IL-33 level in serum, compared to HCs, whereas no significant difference in IL-33 level in serum was showed between asthma children and HCs (adults: SMD 2.17, 95% CI 1.09-3.25; children: SMD 1.81, 95% CI -0.11 to 3.74). The study indicated that moderate and severe asthmatics showed higher IL-33 level in serum, compared to mild asthmatics (SMD 0.78, 95% CI 0.41-1.16, I2 = 66.2%, p = .011). CONCLUSIONS: In conclusion, the main findings of present meta-analysis suggested that there was a significant correlation between IL-33 levels and the severity of asthma. Therefore, IL-33 levels of either serum or plasma may be regarded as a useful biomarker of asthma or the degree of disease.

Relationship between chronotypes and aggression in adolescents: a cross-sectional study.

BACKGROUND: This study aimed to investigate the relationship between chronotypes and aggression in adolescents. METHODS: A cross-sectional study was conducted on 755 primary and secondary school students aged 11-16 years in rural areas of Ningxia Province, China. The Chinese version of the Buss-Perry Aggression Questionnaire (AQ-CV) and the Chinese version Morningness-Eveningness Questionnaire (MEQ-CV) were used to assess the aggressive behavior and chronotypes of the study subjects. The Kruskal-Wallis test was then used to compare the differences in aggression among adolescents with different chronotypes, and Spearman correlation analysis to determine the relationship between chronotypes and aggression. Further linear regression analysis was used to investigate the effects of chronotype, personality traits, family environment, and class environment on adolescent aggression. RESULTS: There were significant differences in chronotypes between different age groups and different sexes. Spearman correlation analysis showed that the MEQ-CV total score was negatively correlated with the AQ-CV total score (r = -0.263) and score of each AQ-CV subscale. In Model 1, chronotypes were negatively associated with aggression when controlling for age and sex, and evening-type adolescents might be more likely to exhibit aggressive behavior (b = -0.513, 95% CI: [-0.712, -0.315], P < 0.001); in Model 2, the negative association remained after controlling for family and class environment on the basis of Model 1 (b = -0.404, 95% CI: [-0.601, -0.208], P < 0.001); and in Model 3, the negative association still existed after controlling for personality traits on the basis of Model 2 (b = -0.383, 95% CI: [-0.577, -0.190], P < 0.001). CONCLUSION: Compared to morning-type adolescents, evening-type adolescents were more likely to exhibit aggressive behavior. Given social expectations for MT adolescents, adolescents should be actively guided to develop a good circadian rhythm that may be more conducive to their physical and mental development.

OsWRKY28 positively regulates salinity tolerance by directly activating OsDREB1B expression in rice.

KEY MESSAGE: OsWRKY28 confers salinity tolerance by directly binding to OsDREB1B promoter and increasing its transcriptional activity, and negatively regulates abscisic acid mediated seedling establishment in rice. WRKY transcription factors have been reported to play a vital role in plants growth, development, abiotic and biotic stress responses. In this study, we explored the functions of a transcription factor OsWRKY28 in rice. The transcript level of OsWRKY28 was strikingly increased under drought, chilling, salt and abscisic acid treatments. The OsWRKY28 overexpression lines showed enhanced salinity stress tolerance, whereas the oswrky28 mutants displayed salt sensitivity compared to wild-type plants. Under salt stress treatment, the expression levels of OsbZIP05, OsHKT1;1 and OsDREB1B were significantly lower yet the level of OsHKT2;1 was significantly higher in oswrky28 mutants than those in wide type plants. Our data of yeast one-hybrid assay and dual-luciferase assay supported that OsWRKY28 could directly bind to the promoter of OsDREB1B to enhance salinity tolerance in rice. In addition, OsWRKY28 overexpression lines displayed hyposensitivity and the oswrky28 mutants showed hypersensitivity compared to wild-type plants under exogenous abscisic acid treatment. Based on the results of yeast two-hybrid assay and GAL4-dependent chimeric transactivation assay, OsWRKY28 physically interacts with OsMPK11 and its transcriptional activity could be regulated by OsMPK11. Together, OsWRKY28 confers salinity tolerance through directly targeting OsDREB1B promoter and further activating its transcription in rice.

Clinical Outcome-Related Cancer Pathways and Mutational Signatures in Patients With Unresectable Esophageal Squamous Cell Carcinoma Treated With Chemoradiotherapy.

PURPOSE: Definitive chemoradiotherapy (dCRT) is a standard-of-care for locally advanced unresectable esophageal squamous cell carcinoma (ESCC). However, even in individuals treated with the same dCRT regimen, differences in the local control rate and radiation-induced thoracic toxicity exist (radiation-induced esophagitis [RIE]). METHODS AND MATERIALS: Here, we describe a comprehensive genomic evaluation of pretreatment tumor tissue samples from 183 patients with ESCC using targeted sequencing of 474 cancer-related genes. The association between endpoints (progression-free survival [PFS], overall survival, locoregional relapse-free survival, distant metastasis-free survival), toxicity (RIE) and genomic features, including altered pathways and the mutational signature, was analyzed. An independent cohort of 84 stage II-III patients with ESCC was used for validation. RESULTS: Gene alterations in the cell cycle pathway were identified in 87% of cases. Other frequently altered pathways included PI3K-AKT (45.9%), NOTCH (38.3%), NRF2 (36.6%), RKT-RAS (28.4%), and homologous recombination repair (HRR; 20.2%). HRR pathway alterations correlated with shortened PFS (mutation vs wild-type: 9.00 vs 14.40 months, hazard ratio, 2.10; 95% confidence interval, 1.29-3.44), while altered RTK-RAS pathways were correlated with worse overall survival in patients with ESCC treated with chemoradiotherapy (mutation vs wild-type: 23.70 vs 33.50 months; hazard ratio, 1.65; 95% confidence interval, 1.01-2.69). Furthermore, enrichment of apolipoprotein B mRNA editing enzyme, catalytic polypeptide (APOBEC) signatures (signatures 2 and 13) was identified in ESCC tumors with altered HRR pathways. High APOBEC signatures and an altered HRR pathway were correlated with poor prognoses in dCRT-treated ESCC. Moreover, the APOBEC signature and/or the presence of HRR pathway alterations were associated with poor PFS and overall survival, which was validated in an independent whole exome sequence cohort. Notably, the altered HRR pathway was also associated with high-grade RIE toxicity in patients with ESCC. CONCLUSIONS: Collectively, our results support the use of comprehensive genomic profiling to guide treatment and minimize RIE in patients with ESCC.

A soybean sodium/hydrogen exchanger GmNHX6 confers plant alkaline salt tolerance by regulating Na+/K+ homeostasis.

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

The OsWRKY63-OsWRKY76-OsDREB1B module regulates chilling tolerance in rice.

Rice (Oryza sativa) is sensitive to low temperatures, which affects the yield and quality of rice. Therefore, uncovering the molecular mechanisms behind chilling tolerance is a critical task for improving cold tolerance in rice cultivars. Here, we report that OsWRKY63, a WRKY transcription factor with an unknown function, negatively regulates chilling tolerance in rice. OsWRKY63-overexpressing rice lines are more sensitive to cold stress. Conversely, OsWRKY63-knockout mutants generated using a CRISPR/Cas9 genome editing approach exhibited increased chilling tolerance. OsWRKY63 was expressed in all rice tissues, and OsWRKY63 expression was induced under cold stress, dehydration stress, high salinity stress, and ABA treatment. OsWRKY63 localized in the nucleus plays a role as a transcription repressor and downregulates many cold stress-related genes and reactive oxygen species scavenging-related genes. Molecular, biochemical, and genetic assays showed that OsWRKY76 is a direct target gene of OsWRKY63 and that its expression is suppressed by OsWRKY63. OsWRKY76-knockout lines had dramatically decreased cold tolerance, and the cold-induced expression of five OsDREB1 genes was repressed. OsWRKY76 interacted with OsbHLH148, transactivating the expression of OsDREB1B to enhance chilling tolerance in rice. Thus, our study suggests that OsWRKY63 negatively regulates chilling tolerance through the OsWRKY63-OsWRKY76-OsDREB1B transcriptional regulatory cascade in rice.

Effect of photooxidation on size distribution, light absorption, and molecular compositions of smoke particles from rice straw combustion.

Organic aerosol (OA) emitted from biomass burning (BB) impacts air quality and global radiation balance. However, the comprehensive characterization of OA remains poorly understood because of the complex evolutionary behavior of OA in atmospheric processes. In this work, smoke particles were generated from rice straw combustion. The effect of OH radicals photooxidation on size distribution, light absorption, and molecular compositions of smoke particles was systematically investigated. The results showed that the median diameters of smoke particles increased by a factor of approximately 1.2 after photooxidation. In the particle compositions, although both non-polar fractions (n-hexane-soluble organic carbon, HSOC) and polar fractions (water-soluble organic carbon, WSOC) underwent photobleaching after aging, the photobleaching properties of HSOC (1.87-2.19) was always higher than that of WSOC (1.52-1.33). Besides, the light-absorbing properties of HSOC were higher than that of WSOC, showing a factor of approximately 1.75 times for mass absorption efficiency at 365 nm (MAE365). Consequently, the simple forcing efficiency (SFE) caused by absorption showed that HSOC has higher radiation effects than WSOC. After photooxidation, the concentration of 16 PAHs in HSOC fractions significantly decreased by 15.3%-72.5%. In WSOC fractions, the content of CHO, CHONS, and CHOS compounds decreased slightly, while the content of CHON compounds increased. Meantime, the variations in molecular properties supported the decrease in light absorption of WSOC fractions. These results reveal the aging behavior of smoke particles, then stress the importance of non-polar organic fractions in particles, providing new insights into understanding the atmospheric pollution caused by BB smoke particles.

Design and Implementation of Charge Pump Phase-Locked Loop Frequency Source Based on GaAs pHEMT Process.

This paper realized a charge pump phase locked loop (CPPLL) frequency source circuit based on 0.15 µm Win GaAs pHEMT process. In this paper, an improved fully differential edge-triggered frequency discriminator (PFD) and an improved differential structure charge pump (CP) are proposed respectively. In addition, a low noise voltage-controlled oscillator (VCO) and a static 64:1 frequency divider is realized. Finally, the phase locked loop (PLL) is realized by cascading each module. Measurement results show that the output signal frequency of the proposed CPPLL is 3.584 GHz-4.021 GHz, the phase noise at the frequency offset of 1 MHz is -117.82 dBc/Hz, and the maximum output power is 4.34 dBm. The chip area is 2701 µm × 3381 µm, and the power consumption is 181 mw.

Light absorption properties and molecular compositions of water-soluble and methanol-soluble organic carbon emitted from wood pyrolysis and combustion.

Organic carbon (OC) emitted from biomass burning (BB) plays an important role in the global radiation budget. In this work, primary OC emitted from wood pyrolysis and combustion under nitrogen (N2) and air conditions in a tube furnace was investigated. The absorption spectra, chemical functional groups, and molecular compositions of OC were analyzed using UV-Vis-NIR spectrophotometer, Fourier transform infrared spectroscopy (FTIR), and Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS), respectively. The light absorption properties showed that the mass absorption efficiency at 365 nm (MAE365) of methanol-soluble OC (MSOC) is 3.1-3.8 times higher than that of water-soluble OC (WSOC). Moreover, the MAE365 values derived from the N2 pyrolysis atmosphere are higher than that from the air atmosphere for both MSOC and WSOC. These results indicated that OC extracted by methanol has higher light absorption, especially for the OC emitted from the N2 pyrolysis atmosphere. Although the FTIR spectra showed identical functional groups for the OC from the air and N2 conditions, molecular compositions from the FT-ICR MS analysis presented significant differences. The molecular weight (MW), double bonds equivalent (DBE), DBE/C, and modified aromaticity index (AImod) of extracted OC showed higher values in MSOC than those in WSOC, and higher values under the N2 atmosphere than those under the air atmosphere. In addition, MAE365 showed positive correlations with MW (r = 0.94), DBE (r = 0.88), DBE/C (r = 0.96), and AImod (r = 0.97), whereas negative correlations with H/C (r = -0.97), O/C (r = -0.90), N/C (r = -0.88), and S/C (r = -0.93). These results indicated that molecules with larger MW and a high level of unsaturation and aromaticity present higher light absorption, while molecules with high elemental ratios of H/C, O/C, N/C, and S/C are adverse to light absorption.

Brain endothelial cells-derived extracellular vesicles overexpressing ECRG4 inhibit glioma proliferation through suppressing inflammation and angiogenesis.

Esophageal cancer related gene-4 (ECRG4) has been shown to be a candidate tumor suppressor in many tumors, but its role in glioma remains poorly understood. This study aimed to explore whether extracellular vesicles (EVs) derived from brain endothelial cells which overexpressed ECRG4 have anti-tumor effect on gliomas in vivo and in vitro, as well as the possible mechanism. A constructed lentivirus expressing the ECRG4 gene was transfected into the hCMEC/D3 cell line. The EVs were isolated from the cells and characterized by Western blot with exosome markers of CD9, CD63, CD81, Alix. RT-PCR and Western blot were performed to verify ECRG4 expression. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and clone formation assays were applied to detect the proliferation of glioma cells incubated with EVs expressing the ECRG4 (ECRG4-exo). The level of inflammatory cytokines and angiogenesis related factors, including nuclear factor kappa-B (NF-κB), interleukin (IL)-1ß, IL-6, IL-8, monocyte chemoattractant protein-1 (MCP-1), hypoxia-inducible factor 1-alpha (HIF-1α), vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor 2 (VEGFR2) levels were detected by ELISA. The T98G cell xenograft mouse model was established and treated with ECRG4-EV. The tumor volume and weight were recorded. p38-MAPK, p-p38-MAPK proteins were determined by Western blot in tumor tissues. As a result, EVs can be internalized into U87MG and T98G cells. ECRG4-EV inhibited U87MG and T98G cell proliferation. ECRG4-EV also inhibited the expression of factors involved in inflammation and angiogenesis. In addition, ECRG4-EVs suppressed tumor growth and decreased the production of inflammatory cytokines through inactivation of p38-MAPK signal pathway. In conclusion, ECRG4-EVsuppresses glioma proliferation through modulating the inflammation and angiogenesis.

[The Expression of WTAP Gene in Acute Myeloid Leukemia and Its Clinical Significance].

OBJECTIVE: To investigate the expression of WTAP gene in acute myeloid leukemia (AML) and its clinical significance. METHODS: 74 acute myeloid leukemia patients with non-M3 type and 19 normal donors were selected, and real-time quantitative polymerase chain reaction was used to detect the mRNA expression level of WTAP gene in their bone marrow cells. The relationship between the mRNA expression level of WTAP gene and the clinical characteristics was analyzed. RESULTS: The relative mRNA expression of WTAP gene in the non-M3 AML group was significantly higher than that in the healthy control group, and the difference showed statistically significant (P<0.01). There showed no statistically significant difference in WTAP gene expression among each subtypes (all P>0.05) according to the classification of FAB. The mRNA expression level of WTAP gene in FLT3-ITD mutated AML patients was higher than that in FLT3-ITD unmutated group (P=0.016), and the mRNA expression level of WTAP gene in AML patients with CEBPα mutation was lower than that in CEBPα unmutated group (P=0.016). The expression level of WTAP mRNA was positively correlated with WT1 expression (r=0.6866, P<0.01). There was no relationship between WTAP mRNA expression level and other clinical parameters, such as age, gender, white blood cell count, hemoglobin level, platelet count, bone marrow original proportion of immature cells, chromosome karyotype, and NPM1, DNMT3A, ASXL1, NRAS, TET2 genes mutation status (P>0.05). The expression level of WTAP mRNA showed no obvious effect on the complete remission of patients after first treatment. The different expression level of WTAP gene at initial diagnosis showed also no effect on the overall survival time of patients. CONCLUSION: The expression level of WTAP gene is increasing in new diagnosed non-M3 acute myeloid leukemia. There is a positive correlation between the expression level of WTAP gene and the expression level of WT1 fusion gene. WTAP mRNA always shows higher expression in patients with FLT3-ITD mutation than that in patients without FLT3-ITD mutation, and shows lower expression in patients with CEBPα mutation than that in unmutated group.

Intercept of minute ventilation versus carbon dioxide output relationship as an index of ventilatory inefficiency in chronic obstructive pulmonary disease.

BACKGROUND: Ventilatory inefficiency contributes to exercise intolerance in chronic obstructive pulmonary disease (COPD). The intercept of the minute ventilation (V˙ E) vs. carbon dioxide output (V˙ CO2) plot is a key ventilatory inefficiency parameter. However, its relationships with lung hyperinflation (LH) and airflow limitation are not known. This study aimed to evaluate correlations between the V˙ E/V˙ CO2 intercept and LH and airflow limitation to determine its physiological interpretation as an index of functional impairment in COPD. METHODS: We conducted a retrospective analysis of data from 53 COPD patients and 14 healthy controls who performed incremental cardiopulmonary exercise tests (CPETs) and resting pulmonary function assessment. Ventilatory inefficiency was represented by parameters reflecting the V˙ E/V˙ CO2 nadir and slope (linear region) and the intercept of V˙ E/V˙ CO2 plot. Their correlations with measures of LH and airflow limitation were evaluated. RESULTS: Compared to control, the slope (30.58±3.62, P<0.001) and intercept (4.85±1.11 L/min, P<0.05) were higher in COPDstages1-2, leading to a higher nadir (31.47±4.47, P<0.01). Despite an even higher intercept in COPDstages3-4 (7.16±1.41, P<0.001), the slope diminished with disease progression (from 30.58±3.62 in COPDstages1-2 to 26.84±4.96 in COPDstages3-4, P<0.01). There was no difference in nadir among COPD groups and higher intercepts across all stages. The intercept was correlated with peak V˙ E/maximal voluntary ventilation (MVV) (r=0.489, P<0.001) and peak V˙ O2/Watt (r=0.354, P=0.003). The intercept was positively correlated with residual volume (RV) % predicted (r=0.571, P<0.001), RV/total lung capacity (TLC) (r=0.588, P<0.001), peak tidal volume (VT)/FEV1 (r=0.482, P<0.001) and negatively correlated with rest inspiratory capacity (IC)/TLC (r=-0.574, P<0.001), peak VT/TLC (r=-0.585, P<0.001), airflow limitation forced expiratory volume in 1 s (FEV1) % predicted (r=-0.606, P<0.001), and FEV1/forced vital capacity (FVC) (r=-0.629, P<0.001). CONCLUSIONS: V˙ E/V˙ CO2 intercept was consistently correlated with worsening static and dynamic LH, pulmonary gas exchange, and airflow limitation in COPD. The V˙ E/V˙ CO2 intercept emerged as a useful index of ventilatory inefficiency in COPD patients.

Identification and co-expression analysis of long noncoding RNAs and mRNAs involved in the deposition of intramuscular fat in Aohan fine-wool sheep.

BACKGROUND: Intramuscular fat (IMF) content has become one of the most important indicators for measuring meat quality, and levels of IMF are affected by various genes. Long non-coding RNAs (lncRNAs) are widely expressed non-coding RNAs that play an important regulatory role in a variety of biological processes; however, research on the lncRNAs involved in sheep IMF deposition is still in its infancy. Aohan fine-wool sheep (AFWS), one of China's most important meat-hair, dual-purpose sheep breed, provides a great model for studying the role of lncRNAs in the regulation of IMF deposition. We identified lncRNAs by RNA sequencing in Longissimus thoracis et lumborum (LTL) samples of sheep at two ages: 2 months (Mth-2) and 12 months (Mth-12). RESULTS: We identified a total of 26,247 genes and 6935 novel lncRNAs in LTL samples of sheep. Among these, 199 mRNAs and 61 lncRNAs were differentially expressed. We then compared the structural characteristics of lncRNAs and mRNAs. We obtained target genes of differentially expressed lncRNAs (DELs) and performed enrichment analyses using Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG). We found that target mRNAs were enriched in metabolic processes and developmental pathways. One pathway was significantly enriched, namely tight junction. Based on the analysis of critical target genes, we obtained seven candidate lncRNAs that potentially regulated lipid deposition and constructed a lncRNA-mRNA co-expression network that included MSTRG.4051.3-FZD4, MSTRG.16157.3-ULK1, MSTRG.21053.3-PAQR3, MSTRG.19941.2-TPI1, MSTRG.12864.1-FHL1, MSTRG.2469.2-EXOC6 and MSTRG.21381.1-NCOA1. We speculated that these candidate lncRNAs might play a role by regulating the expression of target genes. We randomly selected five mRNAs and five lncRNAs to verify the accuracy of the sequencing data by qRT-PCR. CONCLUSIONS: Our study identified the differentially expressed mRNAs and lncRNAs during intramuscular lipid deposition in Aohan fine-wool sheep. The work may widen the knowledge about the annotation of the sheep genome and provide a working basis for investigating intramuscular fat deposition in sheep.

Identification of metabolic biomarkers to predict treatment outcome and disease progression in multiple myeloma.

The relationship between metabolites and multiple myeloma (MM) is becoming a research focus in the field. In this study, we performed metabolic profiling of multiple myeloma and identified potential metabolites associated with clinical characteristics, therapeutic efficacy, and prognosis of the disease. Fifty-five patients with newly-diagnosed multiple myeloma and thirty-seven healthy controls from August 2016 to October 2017 were randomly collected. The serum metabolic profiling was investigated by gas chromatography-mass spectrometry (GC-MS) technique and underwent statistical analysis. Twenty-seven metabolites were found to be significantly different between healthy controls and multiple myeloma patients. Eleven metabolites were significantly elevated, while sixteen metabolites were decreased in the multiple myeloma population. Metabolic changes were also observed in patients with renal impairment and bone destruction. Levels of urea were significantly decreased after treatment while levels of hypotaurine showed significant increase in the good-effect group (P<0.05), but not in the no-good-effect group (P>0.05). In multivariate statistical analyses, high cysteine and high hypotaurine are independent risk factors for poor treatment outcome. After adjustment for critical clinical characteristics, patients with high levels of glycolic acid and xylitol were found to be less likely to experience disease progression. Multiple myeloma demonstrates different metabolic characteristics compared with the healthy population. Among multiple myeloma patients, renal impairment and bone destruction showed additional metabolic characteristics. Cysteine and hypotaurine have value in predicting the treatment outcome, while glycolic acid and xylitol may be important prognostic factors for multiple myeloma.