FOXK2 facilitates the airway remodeling during chronic asthma by promoting glycolysis in a SIRT2-dependent manner.

Asthma is a chronic pulmonary disease with the worldwide prevalence. The structural alterations of airway walls, termed as "airway remodeling", are documented as the core contributor to the airway dysfunction during chronic asthma. Forkhead box transcription factor FOXK2 is a critical regulator of glycolysis, a metabolic reprogramming pathway linked to pulmonary fibrosis. However, the role of FOXK2 in asthma waits further explored. In this study, the chronic asthmatic mice were induced via ovalbumin (OVA) sensitization and repetitive OVA challenge. FOXK2 was upregulated in the lungs of OVA mice and downregulated after adenovirus-mediated FOXK2 silencing. The lung inflammation, peribronchial collagen deposition, and glycolysis in OVA mice were obviously attenuated after FOXK2 knockdown. Besides, the expressions of FOXK2 and SIRT2 in human bronchial epithelial cells (BEAS-2B) were increasingly upregulated upon TGF-ß1 stimulation and downregulated after FOXK2 knockdown. Moreover, the functional loss of FOXK2 remarkably suppressed TGF-ß1-induced epithelial-mesenchymal transition (EMT) and glycolysis in BEAS-2B cells, as manifested by the altered expressions of EMT markers and glycolysis enzymes. The glycolysis inhibitor 2-deoxy-d-glucose (2-DG) inhibited the EMT in TGF-ß1-induced cells, making glycolysis a driver of EMT. The binding of FOXK2 to SIRT2 was validated, and SIRT2 overexpression blocked the FOXK2 knockdown-mediated inhibition of EMT and glycolysis in TGF-ß1-treated cells, which suggests that FOXK2 regulates EMT and glycolysis in TGF-ß1-treated cells in a SIRT2-dependnet manner. Collectively, this study highlights the protective effect of FOXK2 knockdown on airway remodeling during chronic asthma.

The receptor kinase RiSho1 in Rhizophagus irregularis regulates arbuscule development and drought tolerance during arbuscular mycorrhizal symbiosis.

In terrestrial ecosystems, most plant species can form beneficial associations with arbuscular mycorrhizal (AM) fungi. Arbuscular mycorrhizal fungi benefit plant nutrient acquisition and enhance plant tolerance to drought. The high osmolarity glycerol 1 mitogen-activated protein kinase (HOG1-MAPK) cascade genes have been characterized in Rhizophagus irregularis. However, the upstream receptor of the HOG1-MAPK cascade remains to be investigated. We identify the receptor kinase RiSho1 from R. irregularis, containing four transmembrane domains and one Src homology 3 (SH3) domain, corresponding to the homologue of Saccharomyces cerevisiae. Higher expression levels of RiSho1 were detected during the in planta phase in response to drought. RiSho1 protein was localized in the plasma membrane of yeast, and interacted with the HOG1-MAPK module RiPbs2 directly by protein-protein interaction. RiSho1 complemented the growth defect of the yeast mutant ∆sho1 under sorbitol conditions. Knock-down of RiSho1 led to the decreased expression of downstream HOG1-MAPK cascade (RiSte11, RiPbs2, RiHog1) and drought-resistant genes (RiAQPs, RiTPSs, RiNTH1 and Ri14-3-3), hampered arbuscule development and decreased plants antioxidation ability under drought stress. Our study reveals the role of RiSho1 in regulating arbuscule development and drought-resistant genes via the HOG1-MAPK cascade. These findings provide new perspectives on the mechanisms by which AM fungi respond to drought.

Macrolide resistance of Mycoplasma pneumoniae in several regions of China from 2013 to 2019.

This paper retrospectively analysed the prevalence of macrolide-resistant Mycoplasma pneumoniae (MRMP) in some parts of China. Between January 2013 and December 2019, we collected 4,145 respiratory samples, including pharyngeal swabs and alveolar lavage fluid. The highest PCR-positive rate of M. pneumoniae was 74.5% in Beijing, the highest resistance rate was 100% in Shanghai, and Gansu was the lowest with 20%. The highest PCR-positive rate of M. pneumoniae was 74.5% in 2013, and the highest MRMP was 97.4% in 2019; the PCR-positive rate of M. pneumoniae for adults in Beijing was 17.9% and the MRMP was 10.48%. Among the children diagnosed with community-acquired pneumonia (CAP), the PCR-positive and macrolide-resistant rates of M. pneumoniae were both higher in the severe ones. A2063G in domain V of 23S rRNA was the major macrolide-resistant mutation, accounting for more than 90%. The MIC values of all MRMP to erythromycin and azithromycin were ≥ 64 µg/ml, and the MICs of tetracycline and levofloxacin were ≤ 0.5 µg/ml and ≤ 1 µg/ml, respectively. The macrolide resistance varied in different regions and years. Among inpatients, the macrolide-resistant rate was higher in severe pneumonia. A2063G was the common mutation, and we found no resistance to tetracycline and levofloxacin.

The application value of lung ultrasound scoring in assessing disease severity: Evaluation of small-scale outbreaks of COVID-19.

PURPOSE: This study explored the use of transthoracic lung ultrasound for evaluating COVID-19 patients, compared it with computed tomography (CT), and examined its effectiveness using 8 and 12 lung regions. METHODS: A total of 100 patients with COVID-19 and 40 healthy volunteers were assessed using 12 regions (bilateral upper/lower regions of the anterior/lateral/posterior chest) and simplified 8 zones (bilateral upper/lower regions of the anterior/lateral chest) transthoracic lung ultrasound. The relationships between ultrasound, CT, and clinical indicators were analyzed to evaluate the diagnostic value of ultrasound scores in COVID-19. RESULTS: Increased disease severity correlated with increased 8- and 12-zone ultrasound and CT scores (all p < 0.05). The modified 8-zone method strongly correlated with the 12-zone method (Pearson's r = 0.908, p < 0.05). The 8- and 12-zone methods correlated with CT scoring (correlation = 0.568 and 0.635, respectively; p < 0.05). The intragroup correlation coefficients of the 8-zone, 12-zone, and CT scoring methods were highly consistent (intragroup correlation coefficient = 0.718, p < 0.01). The 8-zone ultrasound score correlated negatively with oxygen saturation (rs = 0.306, p < 0.05) and Ca (rs = 0.224, p < 0.05) and positively with IL-6 (rs = 0.0.335, p < 0.05), erythrocyte sedimentation rate (rs = 0.327, p < 0.05), alanine aminotransferase (rs = 0.230, p < 0.05), and aspartate aminotransferase (rs = 0.251, p < 0.05). The 12-zone scoring method correlated negatively with oxygen saturation (rs = 0.338, p < 0.05) and Ca (rs = 0.245, p < 0.05) and positively with IL-6 (rs = 0.354, p < 0.05) and erythrocyte sedimentation rate (rs = 0.495, p < 0.05). CONCLUSION: Lung ultrasound scores represent the clinical severity and have high clinical value for diagnosing COVID-19 pneumonia. The 8-zone scoring method can improve examination efficiency and reduce secondary injuries caused by patient movement.

2021 Update on MRD in acute myeloid leukemia: a consensus document from the European LeukemiaNet MRD Working Party.

Measurable residual disease (MRD) is an important biomarker in acute myeloid leukemia (AML) that is used for prognostic, predictive, monitoring, and efficacy-response assessments. The European LeukemiaNet (ELN) MRD Working Party evaluated standardization and harmonization of MRD in an ongoing manner and has updated the 2018 ELN MRD recommendations based on significant developments in the field. New and revised recommendations were established during in-person and online meetings, and a 2-stage Delphi poll was conducted to optimize consensus. All recommendations are graded by levels of evidence and agreement. Major changes include technical specifications for next-generation sequencing-based MRD testing and integrative assessments of MRD irrespective of technology. Other topics include use of MRD as a prognostic and surrogate end point for drug testing; selection of the technique, material, and appropriate time points for MRD assessment; and clinical implications of MRD assessment. In addition to technical recommendations for flow- and molecular-MRD analysis, we provide MRD thresholds and define MRD response, and detail how MRD results should be reported and combined if several techniques are used. MRD assessment in AML is complex and clinically relevant, and standardized approaches to application, interpretation, technical conduct, and reporting are of critical importance.

Co-targeting BCL-XL and BCL-2 by PROTAC 753B eliminates leukemia cells and enhances efficacy of chemotherapy by targeting senescent cells.

BCL-XL and BCL-2 are key anti-apoptotic proteins and validated cancer targets. 753B is a novel BCL-XL/BCL-2 proteolysis targeting chimera (PROTAC) that targets both BCL-XL and BCL-2 to the von Hippel-Lindau (VHL) E3 ligase, leading to BCLX L/BCL-2 ubiquitination and degradation selectively in cells expressing VHL. Because platelets lack VHL expression, 753B spares on-target platelet toxicity caused by the first-generation dual BCL-XL/BCL-2 inhibitor navitoclax (ABT-263). Here, we report pre-clinical single-agent activity of 753B against different leukemia subsets. 753B effectively reduced cell viability and induced dose-dependent degradation of BCL-XL and BCL-2 in a subset of hematopoietic cell lines, acute myeloid leukemia (AML) primary samples, and in vivo patient-derived xenograft AML models. We further demonstrated the senolytic activity of 753B, which enhanced the efficacy of chemotherapy by targeting chemotherapy-induced cellular senescence. These results provide a pre-clinical rationale for the utility of 753B in AML therapy, and suggest that 753B could produce an added therapeutic benefit by overcoming cellular senescence-induced chemoresistance when combined with chemotherapy.

Role of SYVN1 in the control of airway remodeling in asthma protection by promoting SIRT2 ubiquitination and degradation.

BACKGROUND: Asthma is a heterogenous disease that characterized by airway remodeling. SYVN1 (Synoviolin 1) acts as an E3 ligase to mediate the suppression of endoplasmic reticulum (ER) stress through ubiquitination and degradation. However, the role of SYVN1 in the pathogenesis of asthma is unclear. RESULTS: In the present study, an ovalbumin (OVA)-induced murine model was used to evaluate the effect of SYVN1 on asthma. An increase in SYVN1 expression was observed in the lungs of mice after OVA induction. Overexpression of SYVN1 attenuated airway inflammation, goblet cell hyperplasia and collagen deposition induced by OVA. The increased ER stress-related proteins and altered epithelial-mesenchymal transition (EMT) markers were also inhibited by SYVN1 in vivo. Next, TGF-ß1-induced bronchial epithelial cells (BEAS-2B) were used to induce EMT process in vitro. Results showed that TGF-ß1 stimulation downregulated the expression of SYVN1, and SYVN1 overexpression prevented ER stress response and EMT process in TGF-ß1-induced cells. In addition, we identified that SYVN1 bound to SIRT2 and promoted its ubiquitination and degradation. SIRT2 overexpression abrogated the protection of SYVN1 on ER stress and EMT in vitro. CONCLUSIONS: These data suggest that SYVN1 suppresses ER stress through the ubiquitination and degradation of SIRT2 to block EMT process, thereby protecting against airway remodeling in asthma.

[Preliminary Application of Contrast-Enhanced Ultrasound in the Treatment of Diabetic Ulcers].

Objective: To investigate the role of contrast-enhanced ultrasound (CEUS) in the treatment of diabetic ulcers. Methods: The clinical data of 27 diabetic patients, who underwent CEUS examination of their ulcers in our hospital between April 2021 and July 2022 were collected. Among them, 26 patients suffered from diabetic foot ulcers, 5 of whom underwent amputation during hospitalization, and one patient suffered from hip ulcer. The 27 patients' mean age was (64.08±12.57) years. Fasting blood glucose levels of the patients were 3.36-34.61 mmol/L, with a mean of (10.62±8.77) mmol/L. Their glycosylated hemoglobin levels were 5.80%-10.70%, with an average of 7.96%±1.50%. Philips EPIQ7 ultrasound system with L9-3 linear probe of 3-9 MHz was used. First, the patients' ulcers were examined with conventional ultrasound to observe for abnormal echo. Then, 2.4 mL SonoVue (Bracco, Italy), a contrast agent, was injected intravenously through the elbow to look for effusion/pus, sinus tract, or dead space in the lesion area, and images were acquired. Results: Among the 27 patients, except for 5 with amputation stumps, 22 patients had wound areas ranging from 0.16 cm 2 to 215 cm 2, all being accompanied by sinus tract formation. Ten patients underwent ultrasound examination during their treatment. The positive rate of the results of conventional ultrasound was 50% (5/10) for identifying effusion/pus and pseudoaneurysm in the deep area of ulcers, while the positive rate of CEUS results was 100% (10/10). In addition to the lesions found by conventional ultrasound, CEUS also found large sinus tracts or dead spaces in the deep surface of ulcers in 5 additional patients. Of the 27 patients, 17 underwent ultrasound examination of the healing status of sinus tracts and dead spaces in the deep areas of ulcers before discharge. No sinus tracts in the deep areas of the ulcers were found by conventional ultrasound. However, relatively small dead spaces or sinus tracts in the deep areas of the ulcers were found in 10 patients by CEUS. Conventional ultrasound and CEUS found that 1 patient had a small amount of fluid in the amputation stump. In the remaining 6 patients, no deep sinus tracts in the ulcers were found by either conventional ultrasound or CUES, and the ulcers healed completely. Conclusion: By examining microvascular perfusion in diabetic wounds with CEUS, we can observe the extent of sinus tracts during treatment and whether the sinus tracts have healed or whether there are still dead spaces before patient discharge, which provides support for clinical decision-making concerning the treatment of diabetic ulcers.

Transcriptional regulation of metal metabolism- and nutrient absorption-related genes in Eucalyptus grandis by arbuscular mycorrhizal fungi at different zinc concentrations.

BACKGROUND: Eucalyptus spp. are candidates for phytoremediation in heavy metal (HM)-polluted soils as they can adapt to harsh environments, grow rapidly, and have good economic value. Arbuscular mycorrhizal fungi (AMF) are the most widely distributed plant symbiotic fungi in nature, and they play an important role in promoting the phytoremediation of HM-polluted soils. However, few studies have evaluated the HM detoxification mechanism of E. spp. in symbiosis with AMF, and thus, the molecular mechanism remains unclear. RESULTS: The gene transcription and metabolic pathways of E. grandis were studied with and without inoculation with AMF and at different zinc (Zn) concentrations. Here, we focused on the transcript level of six HM-related gene families (ZNT, COPT/Ctr, YSL, ZIFL and CE). Under high-Zn conditions, thirteen genes (ZNT:2, COPT/Ctr:5, YSL:3, ZIFL:1, CE:2) were upregulated, whereas ten genes (ZNT:3, COPT/Ctr:2, YSL:3, ZIFL:1, CE:1) were downregulated. With AMF symbiosis under high-Zn conditions, ten genes (ZNT:4, COPT/Ctr:2, YSL:3, CE:1) were upregulated, whereas nineteen genes (ZNT:9, COPT/Ctr:2, YSL:3, ZIFL:4, CE:1) were downregulated. Under high-Zn conditions, genes of three potassium-related transporters, six phosphate transporters (PHTs), and two nitrate transporters (NRTs) were upregulated, whereas genes of four potassium-related transporters,four PHTs, and four nitrogen-related transporters were downregulated. With AMF symbiosis under high-Zn conditions, genes of two potassium-related transporters, six ammonium transporters (AMTs) and five PHTs were upregulated, whereas genes of six potassium-related transporters, two AMTs and five PHTs were downregulated. CONCLUSIONS: Our results indicates that AMF increases the resistance of E. grandis to high-Zn stress by improving nutrients uptake and regulating Zn uptake at the gene transcription level. Meanwhile, our findings provide a genome-level resource for the functional assignments of key genes regulated by Zn treatment and AM symbiosis in six HM-associated gene families and macromineral nutrient-related gene families of E. grandis. This may contribute to the elucidation of the molecular mechanisms of the response to Zn stress in E. grandis with AM symbiosis at the aspect of the interaction between HM tolerance and nutrient acquisition.

A multi-layer soft lattice based model for Chinese clinical named entity recognition.

OBJECTIVE: Named entity recognition (NER) is a key and fundamental part of many medical and clinical tasks, including the establishment of a medical knowledge graph, decision-making support, and question answering systems. When extracting entities from electronic health records (EHRs), NER models mostly apply long short-term memory (LSTM) and have surprising performance in clinical NER. However, increasing the depth of the network is often required by these LSTM-based models to capture long-distance dependencies. Therefore, these LSTM-based models that have achieved high accuracy generally require long training times and extensive training data, which has obstructed the adoption of LSTM-based models in clinical scenarios with limited training time. METHOD: Inspired by Transformer, we combine Transformer with Soft Term Position Lattice to form soft lattice structure Transformer, which models long-distance dependencies similarly to LSTM. Our model consists of four components: the WordPiece module, the BERT module, the soft lattice structure Transformer module, and the CRF module. RESULT: Our experiments demonstrated that this approach increased the F1 by 1-5% in the CCKS NER task compared to other models based on LSTM with CRF and consumed less training time. Additional evaluations showed that lattice structure transformer shows good performance for recognizing long medical terms, abbreviations, and numbers. The proposed model achieve 91.6% f-measure in recognizing long medical terms and 90.36% f-measure in abbreviations, and numbers. CONCLUSIONS: By using soft lattice structure Transformer, the method proposed in this paper captured Chinese words to lattice information, making our model suitable for Chinese clinical medical records. Transformers with Mutilayer soft lattice Chinese word construction can capture potential interactions between Chinese characters and words.

Prognostic values of human epididymis protein 4 expression in patients with endometrial cancer: A systematic review and meta-analysis.

BACKGROUND: There is no consensus on the correlation between human epididymis protein 4 (HE4) and prognosis of endometrial cancer (EC). Therefore, we performed a meta-analysis to assess the relationship between HE4 and prognosis of EC. METHODS: In this systematic review and meta-analysis, the databases were searched. Correlation of serum or tissue HE4 with clinicopathological characteristics was determined by odds ratio (OR) or standardized mean difference (SMD) with 95% confidence interval (CI), respectively. The hazard ratio (HR) with 95% CI was calculated to evaluate the correlation between HE4 and survival outcome. RESULTS: A total of 38 published studies were eligible. We found that high levels of serum HE4 were associated with FIGO III-IV stage (SMD = 1.58, 95%CI: 1.18-1.98, p < 0.001), grade 3 (SMD = 0.66, 95%CI: 0.39-0.93, p = 0.001), ≥50% myometrial invasion (SMD = 0.78, 95%CI: 0.58-0.99, p < 0.001), lymphovascular space invasion (SMD = 0.82, 95%CI: 0.54-1.11, p = 0.001), lymph node metastasis (SMD = 1.27, 95%CI: 0.84-1.69, p < 0.001), cervical involvement (SMD = 0.71, 95%CI: 0.43-0.98, p = 0.003), parametrial involvement (SMD = 1.03, 95%CI: 0.71-1.35, p < 0.001) and peritoneal cytology (SMD = 0.49, 95%CI: 0.22-0.75, p < 0.001). High expression of tissue HE4 was only significantly associated with lymph node metastasis (OR = 6.19, 95%CI: 2.07-18.50, p = 0.001). High levels of serum HE4 were significantly associated with poor overall survival (univariate: HR = 3.77, 95%CI: 1.94-7.32, p < 0.001; multivariate: HR = 2.15, 95%CI: 1.65-2.80, p < 0.001) and disease-free survival (univariate: HR = 2.89, 95%CI: 2.14-3.88, p < 0.001; multivariate: HR = 2.31, 95%CI:1.20-2.67, p < 0.001) in EC. Compared with cancer antigen 125, serum HE4 may be a better prognostic indicator for EC. CONCLUSIONS: High HE4 expression is associated with poor prognosis of EC and may be a potential prognostic biomarker for EC.

Lightweight Multiprincipal Element Alloys with Excellent Mechanical Properties at Room and Cryogenic Temperatures.

Lightweight multiprincipal element alloys (MPEAs) are promising candidates for potential application as engineering materials due to their high strength and low density. In this work, lightweight Ti70Al15V15 and Ti80Al10V10 MPEAs were fabricated via vacuum arc melting. The phases of the Ti70Al15V15 alloys consisted of a BCC phase and a small amount of B2 phase while the Ti80Al10V10 alloys displayed a dual-phase structure with BCC and HCP phases. The different phase compositions led to differences in their mechanical properties. When the temperature changed from 298 K to 77 K, the strength of the alloys further increased and maintained a certain plasticity. This is attributed to the increasing lattice friction stress at cryogenic temperature. TEM observation demonstrated that dislocation played a crucial role in plastic deformation for both the Ti70Al15V15 and Ti80Al10V10 alloys. In addition, Ti80Al10V10 exhibited significant work-hardening capabilities. By analyzing the strengthening mechanism of the alloys, the theoretical yield strength was calculated, and the results agreed with the experimental values. The present results provide new insight into developing lightweight MPEAs containing Ti and Al.

Phylogenomic framework of the IRLC legumes (Leguminosae subfamily Papilionoideae) and intercontinental biogeography of tribe Wisterieae.

The inverted repeat-lacking clade (IRLC) is one of the most derived clades within the subfamily Papilionoideae of the legume family, and includes various economically important plants, e.g., chickpeas, peas, liquorice, and the largest genus of angiosperms, Astragalus. Tribe Wisterieae is one of the earliest diverged groups of the IRLC, and its generic delimitation and spatiotemporal diversification needs further clarifications. Based on genome skimming data, we herein reconstruct the phylogenomic framework of the IRLC, and infer the inter-generic relationships and historical biogeography of Wisterieae. We redefine tribe Caraganeae to contain Caragana only, and tribe Astragaleae is reduced to the Erophaca-Astragalean clade. The chloroplast capture scenario was hypothesized as the most plausible explanation of the topological incongruences between the chloroplast CDSs and nuclear ribosomal DNA trees in both the Glycyrrhizinae-Adinobotrys-Wisterieae clade and the Chesneyeae-Caraganeae-Hedysareae clade. A new name, Caragana lidou L. Duan & Z.Y. Chang, is proposed within Caraganeae. Thirteen genera are herein supported within Wisterieae, including a new genus, Villosocallerya L. Duan, J. Compton & Schrire, segregated from Callerya. Our biogeographic analyses suggest that Wisterieae originated in the late Eocene and its most recent common ancestor (MRCA) was distributed in continental southeastern Asia. Lineages of Wisterieae remained in the ancestral area from the early Oligocene to the early Miocene. By the middle Miocene, Whitfordiodendron and the MRCA of Callerya-Kanburia-Villosocallerya Clade became disjunct between the Sunda area and continental southeastern Asia, respectively; the MRCA of Wisteria migrated to North America via the Bering land bridge. The ancestor of Austrocallerya and Padbruggea migrated to the Wallacea-Oceania area, which split in the early Pliocene. In the Pleistocene, Wisteria brachybotrys, W. floribunda and Wisteriopsis japonica reached Japan, and Callerya cinerea dispersed to South Asia. This study provides a solid phylogenomic for further evolutionary/biogeographic/systematic investigations on the ecologically diverse and economically important IRLC legumes.

Ionic liquid-derived Fe, N, S, F multiple heteroatom-doped carbon materials for enhanced oxygen reduction reaction.

Heteroatoms doped carbon catalysts have been intensively studied to take the place of Platinum based catalysts for oxygen reduction reaction (ORR) because of their ideal catalytic activity. Herein, the microporous-mesoporous carbon material catalysts doped with Fe, N, S and F were synthesized through a plain one-pot pyrolysis method with ionic liquid 1-butyl-3-methyli-midazolium bis((trifluoromethyl)sulfonyl)imide ([Bmim][TF2N]) and melamine as precursors. Electrochemical analysis shows that the ORR activity and stability of the obtained catalysts are obviously better than Pt/C under alkaline condition. Meanwhile, the catalysts show similar ORR activity and much better durability in 0.1 M HClO4comparing to Pt/C. Moreover, the tolerance of methanol in both basic and acid solutions is greatly better than Pt/C. The high activity is ascribed to the large specific surface area, porous structure and the synergistic effect between S, F, pyridine N, graphite N and Fe-Nx. The high stability possibly comes from the appropriate graphitization and the carbon-coating effect. The strategy proposed here has the advantages of facile, low cost, high efficiency and easy large-scale production, which provides new ideas for the preparation of high-performance Fe-N-C electrocatalysts.

Contribution of endotoxin to Th17 bias in patients with non-alcoholic steatohepatitis.

Non-alcoholic steatohepatitis (NASH) is a form of non-alcoholic fatty liver disease (NAFLD) with more severe inflammation-induced liver damage. Microbial products, such as endotoxin, may contribute to the pathogenesis of NASH. In this study, we investigated the effect of serum endotoxin on CD4 T cell inflammation. Age and sex-matched non-obese healthy subjects, subjects with non-alcoholic fatty liver (NAFL) but not steatohepatitis, and NASH patients were recruited for this study. The latter two groups were additionally matched in BMI and diabetes status. We first showed that compared to healthy subjects and NAFL patients, NASH patients presented significantly higher levels of serum endotoxin. Concurrently, NASH patients presented a Th17 bias that was associated with high endotoxin levels. To examine whether endotoxin could directly mediate IL-17 expression from CD4 T cells, naive CD4 T cells were stimulated with varying levels of endotoxin. In healthy subjects and NAFL patients, endotoxin did not act directly on naive CD4 T cells but required the presence of antigen-presenting cells to upregulate IL-17. Inhibition of TLR4 in macrophages, but not in CD4 T cells, could impair endotoxin-mediated IL-17 upregulation. In NASH patients, however, endotoxin at high levels directly, but minimally, increased IL-17 production. We further found that naive CD4 T cells from NASH patients presented significantly higher TLR4 than naive CD4 T cells from healthy subjects and NAFL patients, and CD3/CD28 stimulation could significantly elevate TLR4 expression by naive CD4 T cells. Overall, these data demonstrate that endotoxin promote Th17 bias in NASH patients.

Concomitant targeting of BCL2 with venetoclax and MAPK signaling with cobimetinib in acute myeloid leukemia models.

The pathogenesis of acute myeloid leukemia (AML) involves serial acquisition of mutations controlling several cellular processes, requiring combination therapies affecting key downstream survival nodes in order to treat the disease effectively. The BCL2 selective inhibitor venetoclax has potent anti-leukemia efficacy; however, resistance can occur due to its inability to inhibit MCL1, which is stabilized by the MAPK pathway. In this study, we aimed to determine the anti-leukemia efficacy of concomitant targeting of the BCL2 and MAPK pathways by venetoclax and the MEK1/2 inhibitor cobimetinib, respectively. The combination demonstrated synergy in seven of 11 AML cell lines, including those resistant to single agents, and showed growth-inhibitory activity in over 60% of primary samples from patients with diverse genetic alterations. The combination markedly impaired leukemia progenitor functions, while maintaining normal progenitors. Mass cytometry data revealed that BCL2 protein is enriched in leukemia stem/progenitor cells, primarily in venetoclax-sensitive samples, and that cobimetinib suppressed cytokine-induced pERK and pS6 signaling pathways. Through proteomic profiling studies, we identified several pathways inhibited downstream of MAPK that contribute to the synergy of the combination. In OCI-AML3 cells, the combination downregulated MCL1 protein levels and disrupted both BCL2:BIM and MCL1:BIM complexes, releasing BIM to induce cell death. RNA sequencing identified several enriched pathways, including MYC, mTORC1, and p53 in cells sensitive to the drug combination. In vivo, the venetoclax-cobimetinib combination reduced leukemia burden in xenograft models using genetically engineered OCI-AML3 and MOLM13 cells. Our data thus provide a rationale for combinatorial blockade of MEK and BCL2 pathways in AML.

Determinants of response to bronchodilator in patients with cough variant asthma- A randomized, single-blinded, placebo-controlled study.

BACKGROUND: Not all patients with cough variant asthma (CVA) show responsiveness to bronchodilators (RB) in clinic. Whether there are specific clinical and pathophysiological features can indicate RB in patients with CVA needs further investigation. Thus, we aimed to investigate the RB in patients with CVA and associated factors. METHODS: Forty-two CVA patients were randomized in a 2:1 ratio to receive oral bambuterol hydrochloride (10 mg, once daily, for 3 days) or matched placebo, 36 patients (24 with bronchodilator and 12 with placebo) completed the study eventually. RB was considered when cough visual analogue scale (VAS) score decreased 30% or more after 3 days treatment. The baseline clinical and pathophysiological characteristics between patients with RB and patients without RB were compared. CRS was presented with the lowest concentration of capsaicin inducing at least 5 coughing (C5). RESULTS: The responsive rate of patients with bronchodilator was significantly higher than that with placebo (62.5% vs 16.7%, p < 0.01). Patients with RB showed a significant greater mean decline of FEV1% predicted after bronchial provocation (26.7% vs 22.4%, p < 0.05) and higher geometric mean of sputum eosinophils (1.37 vs 0.69, p < 0.05) as compared with these without RB. No significant differences in sputum neutrophil, Log C5 were found between patients with RB and patients without RB. There was a moderate correlation between the decline of FEV1% pred and RB (rs = 0.443, p < 0.05). The regression analysis showed that nocturnal cough was a predictor of RB (OR, 7.33, 95% CI: 1.11-48.26, p = 0.038). No adverse events were reported by all of the patients after the study. CONCLUSION: More than one-third of patients with CVA do not respond to bronchodilator treatment, indicating that the response to bronchodilator should not be a diagnostic requirement of CVA. CVA patients with higher airway responsiveness will more likely respond to bronchodilator. Cough of CVA might be elicited by different mechanisms, which suggests that CVA could be divided into two phenotypes according to the response to bronchodilators.

Effects of cigarette smoking on older chinese men treated with clopidogrel monotherapy or aspirin monotherapy: a prospective study.

We investigated the comparative effects of smoking status on outcomes in older Chinese men receiving aspirin or clopidogrel monotherapy. This was a prospective observational study of outcomes in 668 men aged ≥ 60 years undergoing annual health examination in the Chinese People's Liberation Army General Hospital from March-April 2017. All patients received regular treatment with aspirin or clopidogrel. Platelet aggregation and phenotyping for rs762551 were measured in all patients. We recorded all major adverse cardiovascular and cerebrovascular events; namely, all-cause death, myocardial infarction, stroke, transient ischemic attack, and unstable angina. In the clopidogrel subgroup, homozygous carriers (AA) of the CYP1A2*1F gene (rs762551, 163C>A) appeared more frequently in smokers than in nonsmokers (45.6% vs 32.7%, p = .035). Adenosine diphosphate-induced platelet aggregation using light transmittance aggregometry was lower in smokers compared with nonsmokers (44.97 ± 20.05% vs 51.98 ± 19.38%, respectively; p = .0018). Smokers (n = 103) had a decreased risk of major adverse cardiovascular and cerebrovascular events, compared with nonsmokers [n = 159; hazard ratio, 0.466; 95% confidence interval: 0.262-0.829, p = .008]. In the aspirin subgroup, AA-induced platelet aggregation showed no significant difference regarding smoking vs nonsmoking status (30.90 ± 32.21 vs 29.78 ± 31.47, respectively; p = .771). However, we saw a significant increase in adverse clinical events in the smoking group (n = 148) compared with the nonsmoking group (n = 258; hazard ratio = 1.907, 95% confidence interval: 1.128-3.225; p = .016). In older Chinese men, active smokers benefitted from clopidogrel therapy compared with aspirin. Long-term cigarette smoking may contribute to increased variations in CYP1A2*1F, but the variations do not fully explain the smoking paradox.

11-Methoxytabersonine Induces Necroptosis with Autophagy through AMPK/mTOR and JNK Pathways in Human Lung Cancer Cells.

Aspidosperma alkaloids, a subclass of monoterpenoid indole alkaloids rich in the Apocynaceae plants, possess remarkable antitumor activities, but the underlying mechanisms have rarely been reported. In the current project, 11-methoxytabersonine (11-MT), an aspidosperma-type alkaloid isolated from Tabernaemontana bovina, significantly inhibited the viability of two human lung cancer cell lines A549 and H157, and the molecular mechanisms were thus investigated. The results showed that 11-MT killed lung cancer cells via induction of necroptosis in an apoptosis-independent manner. In addition, 11-MT strongly induced autophagy in the two cell lines, which played a protective role against 11-MT-induced necroptosis. Finally, the autophagy caused by 11-MT was found to be via activation of the AMP activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) and the c-Jun N-terminal kinase (JNK) signaling pathways in both cells. Taken together, 11-MT exhibited an antitumor mechanism different from that of previously reported analogues and could have the potential to serve as a lead compound for the development of new chemotherapy for lung cancer.

Effects of calcium magnesium phosphate fertilizer, biochar and spent mushroom substrate on compost maturity and gaseous emissions during pig manure composting.

This study used a laboratory-scale system to investigate the effects of calcium magnesium phosphate fertilizer (CaMgP), biochar, and spent mushroom substrate (SMS) on compost maturity and gasous emissions during pig manure composting. The results showed that the addition of CaMgP, Biochar or SMS had no negative effect on the quality and maturity of compost, and all three additives could reduce the emissions of ammonia (NH3), hydrogen sulfide (H2S), dimethyl sulfide (Me2S) and dimethyl disulfide (Me2SS). Among them, the effect of adding CaMgP on NH3 emission reduction was the most obvious, reduced 42.90%. The emission reduction of CaMgP to H2S was similar to that of SMS, which decreased by 34.91% and 32.88% respectively. The emission reduction effects of the three additives on Me2S and Me2SS were obvious, all of which were over 50%. However, only adding SMS reduced the N2O emission by 37.08%.