A soybean bZIP transcription factor is involved in submergence resistance.

Although the functions of basic leucine zipper (bZIP) family transcription factors in the regulation of various abiotic stresses are beginning to be unveiled, the precise roles of bZIP proteins in plants coping with submergence stress remain unclear. Here we identified a bZIP gene GmbZIP71-4 from soybean, which localized in the nucleus. The GmbZIP71-4 over-expressed tabocco line showed reduced submergence resistance due to the decreased abscisic acid (ABA) content. GO and KEGG pathway analysis based on chromatin immunoprecipitation assay sequencing (ChIP-seq) indicated that the differences expressed genes between submergence treatment and control groups were specially enriched in plant hormone signal transduction items, especially those in response to ABA. Electrophoretic mobility shift assays (EMSA) demonstrated that GmbZIP71-4 bound to the promoter of GmABF2 gene, which is consistent with the ChIP-qPCR results. GmbZIP71-4 function as a negative regulator of soybean in responding to submergence stress through manipulating ABA signaling pathway. This findings will set a solid foundation for the understanding of submergence resistance in plants.

Endothelial cell-released extracellular vesicles trigger pyroptosis and vascular inflammation to induce atherosclerosis through the delivery of HIF1A-AS2.

Extracellular vesicles (EVs) possess great potential in the modulation of cardiovascular diseases. Our current work intended to assay the clinical significance of endothelial cell (EC)-derived EVs in atherosclerosis (AS). Expression of HIF1A-AS2, miR-455-5p, and ESRRG in plasma from AS patients and mice and EVs from ox-LDL-treated ECs was measured. Interactions among HIF1A-AS2, miR-455-5p, ESRRG, and NLRP3 were analyzed. Next, EVs were co-cultured with ECs, and ectopic expression and depletion experimentations of HIF1A-AS2, miR-455-5p, ESRRG, and/or NLRP3 were carried out to assay their roles in pyroptosis and inflammation of ECs in AS. At last, the effects of HIF1A-AS2 shuttled by EC-derived EVs on EC pyroptosis and vascular inflammation in AS were verified in vivo. HIF1A-AS2 and ESRRG were highly expressed, while miR-455-5p was poorly expressed in AS. HIF1A-AS2 could sponge miR-455-5p to elevate the expression of ESRRG and NLRP3. Both in vitro and in vivo experiments revealed that ECs-derived EVs carrying HIF1A-AS2 induced the pyroptosis and vascular inflammation of ECs to promote the progression of AS by sponging miR-455-5p via ESRRG/NLRP3. HIF1A-AS2 shuttled by ECs-derived EVs can accelerate the progression of AS by downregulating miR-455-5p and upregulating ESRRG and NLRP3.

Dress me an outfit: advanced probiotics hybrid systems for intelligent IBD therapy.

Inflammation bowel disease (IBD) has emerged as a public health challenge worldwide; with high incidence and rapid prevalence, it has troubled billions of people and further induced multitudinous systemic complications. Recent decade has witnessed the vigorous application of food-borne probiotics for IBD therapy; however, the complicated and changeable environments of digestive tract have forced probiotics to face multiple in vivo pressures, consequently causing unsatisfied prophylactic or therapeutic efficacy attributed to off-targeted arrival, damaged viability, insufficient colonization efficiency, etc. Fortunately, arisen hybrid technology has provided versatile breakthroughs for the targeted transplantation of probiotics. By ingeniously modifying probiotics to form probiotics hybrid systems (PHS), the biological behaviors of probiotics in vivo could be mediated, the interactions between probiotics with intestinal components can be facilitated, and diverse advanced probiotic-based therapies for IBD challenge can be developed, which attribute to the intelligent response to microenvironment of PHS, and intelligent design of PHS for multiple functions combination. In this review, various PHS were categorized and their intestinal behaviors were elucidated systematically, their therapeutic effects and intrinsic mechanism were further analyzed. Besides, shortages of present PHS and the corresponding solutions have been discussed, based on which the future perspectives of this field have also been proposed. The undeniable fact is that PHS show an incomparable future to bring the next generation of advanced food science.

Dressing probiotics with versatile outfits would impart them with extended functions, including elevated targeted efficiency to the nidi, controlled in situ release, enhance intestinal colonization, comprehensive microecology regulation, and so on. In this article, we systematically analyzed and categorized PHS for intelligent IBD therapy published in recent decade, and discussed their pros and cons to further raise the future orientation for PHS development.

A wild rice CSSL population facilitated identification of salt tolerance genes and rice germplasm innovation.

Salt stress is one of the major factors that limits rice production. Therefore, identification of salt-tolerant alleles from wild rice is important for rice breeding. In this study, we constructed a set of chromosome segment substitution lines (CSSLs) using wild rice as the donor parent and cultivated rice Nipponbare (Nip) as the recurrent parent. Salt tolerance germinability (STG) was evaluated, and its association with genotypes was determined using this CSSL population. We identified 17 QTLs related to STG. By integrating the transcriptome and genome data, four candidate genes were identified, including the previously reported AGO2 and WRKY53. Compared with Nip, wild rice AGO2 has a structure variation in its promoter region and the expression levels were upregulated under salt treatments; wild rice WRKY53 also has natural variation in its promoter region, and the expression levels were downregulated under salt treatments. Wild rice AGO2 and WRKY53 alleles have combined effects for improving salt tolerance at the germination stage. One CSSL line, CSSL118 that harbors these two alleles was selected. Compared with the background parent Nip, CSSL118 showed comprehensive salt tolerance and higher yield, with improved transcript levels of reactive oxygen species scavenging genes. Our results provided promising genes and germplasm resources for future rice salt tolerance breeding.

Effects of Bifidobacterium breve 207-1 on regulating lifestyle behaviors and mental wellness in healthy adults based on the microbiome-gut-brain axis: a randomized, double-blind, placebo-controlled trial.

PURPOSE: Our study aimed to explore the efficacy of Bifidobacterium breve 207-1 on specific neurotransmitters and hormones and the ability to regulate lifestyle behaviors in healthy adults. METHODS: In total, 120 healthy adults with high mental stress, overweight, insomnia, and constipation were randomly assigned to receive low-dose B. breve 207-1 (LD, n = 40), high-dose B. breve 207-1 (HD, n = 40), or placebo (n = 40) for 28 days. Fecal and blood samples were collected and questionnaires were answered before and after the trial. Neurotransmitters and serum hormones were detected using enzyme-linked immunosorbent assay. The gut microbiota composition was assessed using 16 S rRNA sequencing. Short-chain fatty acids (SCFAs) concentrations were determined via gas chromatography-mass spectrometry (GC-MS). RESULTS: The primary outcome of our study was changes in mental wellness, including neurotransmitters, the hypothalamic-pituitary-adrena (HPA) axis hormones, and the psychological scales. The results showed that γ-aminobutyric acid (GABA) increased significantly and the HPA axis hormones were suppressed overall in the probiotic groups while 5-hydroxytryptamine (5-HT) did not change significantly. However, there was no significant change in mood scale scores. The secondary outcome focused on the ability of 207-1 to regulate the body and lifestyle of healthy adults (e.g., sleep, diet, exercise, etc.). The PSQI scores in the probiotics groups significantly decreased, indicating improved sleep quality. Meanwhile, the probiotic groups had a slight increase in exercise consumption while dietary intake stabilized. By physical examination, the participants showed weight loss although no statistically significant difference was observed between the groups. Then, validated by gut microbiota, changes in the gut microbiota were observed under the effective intervention of 207-1 while short-chain fatty acids (SCFAs) increased in the LD group, particularly acetic and propionic acids. There was a slight decrease in alpha-diversity in the HD group. CONCLUSION: Bifidobacterium breve 207-1 entered the organism and affected neurotransmitter and the HPA axis hormone levels via the microbiome-gut-brain axis. Meanwhile, 207-1 supplementation improved daily lifestyle behaviors in healthy adults, which may in turn lead to changes in their bodies (e.g. weight and lipid metabolism). However, this study did not find significant mood-modulating efficacy. The mechanism of the overall study is unclear, but we hypothesize that SCFAs may be the key pathway, and more experiments are needed for validation in the future. TRIAL REGISTRATION: This trial was retrospectively registered in the Chinese Clinical Trial Registry under the accession number ChiCTR2300069453 on March 16, 2023.

A pH-triggered N-oxide polyzwitterionic nano-drug loaded system for the anti-tumor immunity activation research.

Triple negative breast cancer (TNBC) has the characteristics of low immune cell infiltration, high expression of tumor programmed death ligand 1 (PD-L1), and abundant cancer stem cells. Systemic toxicity of traditional chemotherapy drugs due to poor drug selectivity, and chemotherapy failure due to tumor drug resistance and other problems, so it is particularly important to find new cancer treatment strategies for TNBC with limited treatment options. Both the anti-tumor natural drugs curcumin and ginsenoside Rg3 can exert anti-tumor effects by inducing immunogenic cell death (ICD) of tumor cells, reducing PD-L1 expression, and reducing cancer stem cells. However, they have the disadvantages of poor water solubility, low bioavailability, and weak anti-tumor effect of single agents. We used vinyl ether bonds to link curcumin (Cur) with N-O type zwitterionic polymers and at the same time encapsulated ginsenoside Rg3 to obtain hyperbranched zwitterionic drug-loaded micelles OPDEA-PGED-5HA@Cur@Rg3 (PPH@CR) with pH response. In vitro cell experiments and in vivo animal experiments have proved that PPH@CR could not only promote the maturation of dendritic cells (DCs) and increase the CD4+ T cells and CD8+ T cells by inducing ICD in tumor cells but also reduce the expression of PD-L1 in tumor tissues, and reduce cancer stem cells and showed better anti-tumor effects and good biological safety compared with free double drugs, which is a promising cancer treatment strategy.

Deep learning based detection and classification of fetal lip in ultrasound images.

OBJECTIVES: Fetal cleft lip is a common congenital defect. Considering the delicacy and difficulty of observing fetal lips, we have utilized deep learning technology to develop a new model aimed at quickly and accurately assessing the development of fetal lips during prenatal examinations. This model can detect ultrasound images of the fetal lips and classify them, aiming to provide a more objective prediction for the development of fetal lips. METHODS: This study included 632 pregnant women in their mid-pregnancy stage, who underwent ultrasound examinations of the fetal lips, collecting both normal and abnormal fetal lip ultrasound images. To improve the accuracy of the detection and classification of fetal lips, we proposed and validated the Yolov5-ECA model. RESULTS: The experimental results show that, compared with the currently popular 10 models, our model achieved the best results in the detection and classification of fetal lips. In terms of the detection of fetal lips, the mAP@0.5 and mAP@0.5:0.95 were 0.920 and 0.630, respectively. In the classification of fetal lip ultrasound images, the accuracy reached 0.925. CONCLUSIONS: The deep learning algorithm has accuracy consistent with manual evaluation in the detection and classification process of fetal lips. This automated recognition technology can provide a powerful tool for inexperienced young doctors, helping them to accurately conduct examinations and diagnoses of fetal lips.

The Hdc GC box is critical for Hdc gene transcription and histamine-mediated anaphylaxis.

BACKGROUND: Histamine is a critical mediator of anaphylaxis, a neurotransmitter, and a regulator of gastric acid secretion. Histidine decarboxylase is a rate-limiting enzyme for histamine synthesis. However, in vivo regulation of Hdc, the gene that encodes histidine decarboxylase, is poorly understood. OBJECTIVE: We sought to investigate how enhancers regulate Hdc gene transcription and histamine synthesis in resting conditions and in a mouse model of anaphylaxis. METHODS: H3K27 acetylation histone modification and chromatin accessibility were used to identify candidate enhancers. The enhancer activity of candidate enhancers was measured in a reporter gene assay, and the function enhancers were validated by CRISPR deletion. RESULTS: Deletion of the GC box, which binds to zinc finger transcription factors, in the proximal Hdc enhancer reduced Hdc gene transcription and histamine synthesis in mouse and human mast cell lines. Mast cells, basophils, brain cells, and stomach cells from GC box-deficient mice transcribed the Hdc gene much less than similar cells from wild-type mice, and Hdc GC box-deficient mice failed to develop anaphylaxis. CONCLUSION: The HDC GC box within the proximal enhancer in the mouse and human HDC gene is essential for Hdc gene transcription, histamine synthesis, and histamine-mediated anaphylaxis in vitro and in vivo.

Amorphization-Induced Cation Exchange in Indium Oxide Nanosheets for CO2-to-Ethanol Conversion.

Cation exchange (CE) in metal oxides under mild conditions remains an imperative yet challenging goal to tailor their composition and enable practical applications. Herein, we first develop an amorphization-induced strategy to achieve room-temperature CE for universally synthesizing single-atom doped In2O3 nanosheets (NSs). Density functional theory (DFT) calculations elucidate that the abundant coordination-unsaturated sites present in a-In2O3 NSs are instrumental in surmounting the energy barriers of CE reactions. Empirically, a-In2O3 NSs as the host materials successfully undergo exchange with unary cations (Cu2+, Co2+, Mn2+, Ni2+), binary cations (Co2+Mn2+, Co2+Ni2+, Mn2+Ni2+), and ternary cations (Co2+Mn2+Ni2+). Impressively, high-loading single-atom doped (over 10 atom %) In2O3 NSs were obtained. Additionally, Cu/a-In2O3 NSs exhibit an excellent ethanol yield (798.7 µmol g-1 h-1) with a high selectivity of 99.5% for the CO2 photoreduction. This work offers a new approach to induce CE reactions in metal oxides under mild conditions and constructs scalable single-atom doped catalysts for critical applications.

Ruthenium Nanoclusters and Single Atoms on α-MoC/N-Doped Carbon Achieves Low-Input/Input-Free Hydrogen Evolution via Decoupled/Coupled Hydrazine Oxidation.

The hydrazine oxidation-assisted H2 evolution method promises low-input and input-free hydrogen production. However, developing high-performance catalysts for hydrazine oxidation (HzOR) and hydrogen evolution (HER) is challenging. Here, we introduce a bifunctional electrocatalyst α-MoC/N-C/RuNSA, merging ruthenium (Ru) nanoclusters (NCs) and single atoms (SA) into cubic α-MoC nanoparticles-decorated N-doped carbon (α-MoC/N-C) nanowires, through electrodeposition. The composite showcases exceptional activity for both HzOR and HER, requiring -80 mV and -9 mV respectively to reach 10 mA cm-2. Theoretical and experimental insights confirm the importance of two Ru species for bifunctionality: NCs enhance the conductivity, and its coexistence with SA balances the H ad/desorption for HER and facilitates the initial dehydrogenation during the HzOR. In the overall hydrazine splitting (OHzS) system, α-MoC/N-C/RuNSA excels as both anode and cathode materials, achieving 10 mA cm-2 at just 64 mV. The zinc hydrazine (Zn-Hz) battery assembled with α-MoC/N-C/RuNSA cathode and Zn foil anode can exhibit 97.3 % energy efficiency, as well as temporary separation of hydrogen gas during the discharge process. Therefore, integrating Zn-Hz with OHzS system enables self-powered H2 evolution, even in hydrazine sewage. Overall, the amalgamation of NCs with SA achieves diverse catalytic activities for yielding multifold hydrogen gas through advanced cell-integrated-electrolyzer system.

IL-33 priming and antigenic stimulation synergistically promote the transcription of proinflammatory cytokine and chemokine genes in human skin mast cells.

BACKGROUND: Antigenic stimulation through cross-linking the IgE receptor and epithelial cell-derived cytokine IL-33 are potent stimuli of mast cell (MC) activation. Moreover, IL-33 primes a variety of cell types, including MCs to respond more vigorously to external stimuli. However, target genes induced by the combined IL-33 priming and antigenic stimulation have not been investigated in human skin mast cells (HSMCs) in a genome-wide manner. Furthermore, epigenetic changes induced by the combined IL-33 priming and antigenic stimulation have not been evaluated. RESULTS: We found that IL-33 priming of HSMCs enhanced their capacity to promote transcriptional synergy of the IL1B and CXCL8 genes by 16- and 3-fold, respectively, in response to combined IL-33 and antigen stimulation compared to without IL-33 priming. We identified the target genes in IL-33-primed HSMCs in response to the combined IL-33 and antigenic stimulation using RNA sequencing (RNA-seq). We found that the majority of genes synergistically upregulated in the IL-33-primed HSMCs in response to the combined IL-33 and antigenic stimulation were predominantly proinflammatory cytokine and chemokine genes. Moreover, the combined IL-33 priming and antigenic stimulation increase chromatin accessibility in the synergy target genes but not synergistically. Transcription factor binding motif analysis revealed more binding sites for NF-κB, AP-1, GABPA, and RAP1 in the induced or increased chromatin accessible regions of the synergy target genes. CONCLUSIONS: Our study demonstrates that IL-33 priming greatly potentiates MCs' ability to transcribe proinflammatory cytokine and chemokine genes in response to antigenic stimulation, shining light on how epithelial cell-derived cytokine IL-33 can cause exacerbation of skin MC-mediated allergic inflammation.

Cucumis sativus PHLOEM PROTEIN 2-A1 like gene positively regulates salt stress tolerance in cucumber seedlings.

PHLOEM PROTEIN 2-A1 like (PP2-A1) gene is a member of the PP2 multigene family, and the protein encoded by which has the function of stress defense. Based on our previous proteomic study of cucumber phloem sap, CsPP2-A1 protein expression was significantly enriched under salt stress. In this paper, we obtained CsPP2-A1 interfering (CsPP2-A1-RNAi) cucumber by Agrobacterium tumefaciens-mediated method. The phenotypic changes of wild-type (WT) cucumber, CsPP2-A1-overexpressing (OE) cucumber, and CsPP2-A1-RNAi cucumber under salt treatment were observed and compared. Furthermore, physiological indicators were measured in four aspects: osmoregulation, membrane permeability, antioxidant system, and photosynthetic system. The analysis of contribution and correlation for each variable were conducted by principal component analysis (PCA) and Pearson's correlation coefficient. The above results showed that CsPP2-A1-RNAi cucumber plants exhibited weaker salt tolerance compared to WT cucumber and CsPP2-A1-OE cucumber plants in terms of phenotype and physiological indicators in response to salt stress, while CsPP2-A1-OE cucumber always showed the robust salt tolerance. Together, these results indicated that CsPP2-A1 brought a salinity tolerance ability to cucumber through osmoregulation and reactive oxygen species (ROS) homeostasis. The results of the study provided evidence for the function of CsPP2-A1 in plant salt tolerance enhancement, and they will serve as a reference for future salt-tolerant cucumber genetic manipulation.

OTUB1 alleviates NASH through inhibition of the TRAF6-ASK1 signaling pathways.

BACKGROUND AND AIMS: NAFLD is considered as the hepatic manifestation of the metabolic syndrome, which includes insulin resistance, obesity and hyperlipidemia. NASH is a progressive stage of NAFLD with severe hepatic steatosis, hepatocyte death, inflammation, and fibrosis. Currently, no pharmacological interventions specifically tailored for NASH are approved. Ovarian tumor domain, ubiquitin aldehyde binding 1 (OTUB1), the founding member of deubiquitinases, regulates many metabolism-associated signaling pathways. However, the role of OTUB1 in NASH is unclarified. METHODS AND RESULTS: We demonstrated that mice with Otub1 deficiency exhibited aggravated high-fat diet-induced and high-fat high-cholesterol (HFHC) diet-induced hyperinsulinemia and liver steatosis. Notably, hepatocyte-specific overexpression of Otub1 markedly alleviated HFHC diet-induced hepatic steatosis, inflammatory responses, and liver fibrosis. Mechanistically, we identified apoptosis signal-regulating kinase 1 (ASK1) as a key candidate target of OTUB1 through RNA-sequencing analysis and immunoblot analysis. Through immunoprecipitation-mass spectrometry analysis, we further found that OTUB1 directly bound to tumor necrosis factor receptor-associated factor 6 (TRAF6) and suppressed its lysine 63-linked polyubiquitination, thus inhibiting the activation of ASK1 and its downstream pathway. CONCLUSIONS: OTUB1 is a key suppressor of NASH that inhibits polyubiquitinations of TRAF6 and attenuated TRAF6-mediated ASK1 activation. Targeting the OTUB1-TRAF6-ASK1 axis may be a promising therapeutic strategy for NASH.

Neuroimaging markers of early neurological deterioration in acute isolated pontine infarction.

BACKGROUND: Imaging indicators of early neurological deterioration (END) in patients with acute isolated pontine infarctions (AIPI) remained ambiguous. We aimed to find more specific neuroimaging markers for the development of END in patients with AIPI. METHODS: Patients with AIPI within 72 h of stroke onset were screened from a stroke database from January 2018 to July 2021 in the First Affiliated Hospital of Zhengzhou University. Clinical characteristics, laboratory tests, and imaging parameters were collected. The layers having the largest infarct area on diffusion-weighted imaging (DWI) and T2 sequences were chosen. On the transverse plane of DWI and sagittal plane of T2-Flair images, the maximum length (a, m) and maximum width (b, n) vertical to the length of the infarcted lesions were measured respectively. On the sagittal plane of T2-Flair image, the maximum ventrodorsal length (f) and rostrocaudal thickness (h) were measured. On the sagittal plane, lesions were evenly split into upper, middle, and lower types based on the lesion's location in the pons. The ventral and dorsal types of location were separated based on whether the ventral borders of the pons were involved on transvers plane. END was defined as a ≥2 point increase in the National Institutes of Health Stroke Scale (NIHSS) total score or a ≥1 point increase in the motor items within 72 h after admission. Multivariate logistic regression analyses were used to explore risk factors associated with END. The receiver operating characteristic (ROC) curve analysis and the area under the curve (AUC) was performed to estimate the discriminative power and determine the optimal cut-off points of imaging parameters on the prediction of END. RESULTS: A total of 218 patients with AIPI were included in the final analysis. END occurred in 61 cases (28.0%). Multivariate logistic regression analysis showed that the ventral type of lesion location was associated with END in all models adjusted. In addition, in Model 1, b (odds ratio (OR) 1.145, 95% confidence interval (95% CI), 1.007-1.301) and n (OR 1.163, 95% CI 1.012-1.336); in Model 2, b*n (OR 1.010, 95% CI 1.002-1.018); in Model 3, n (OR 1.179, 95% CI, 1.028-1.353); and in Model 4, b (OR 1.143, 95% CI 1.006-1.298) and n (OR 1.167, 95% CI 1.016-1.341) were found to be associated with END respectively after different adjustments. ROC curve analysis with END showed that the AUC, the optimal cut-off value, and its sensitivity and specificity were 0.743 (0.671-0.815), 9.850 mm, and 68.9% and 79.0% for b; 0.724 (0.648-0.801), 10.800 mm, and 57.4% and 80.9% for n; and 0.772 (0.701-0.842), 108.274 mm2, and 62.3% and 85.4% for b*n, respectively (b*n vs b: P =0.213; b*n vs n: P =0.037; b vs n: P =0.645). CONCLUSIONS: Our study revealed that besides the ventral type of lesion location, the maximum width of lesion on the transverse plane of DWI and sagittal plane of T2 image (b, n) may be imaging markers for the development of END in AIPI patients, and the product of the two (b*n) showed a better prediction value on the risks of END.

Broadening the Substrate Specificity of Cellobiose Phosphorylase from Clostridium thermocellum for Improved Transformation of Cellodextrin to Starch.

Cellobiose phosphorylase (CBP) catalyzes the reversible phosphorolysis of cellobiose into α-glucose 1-phosphate and glucose. A CBP with a broadened substrate specificity would be more desirable when utilized to convert cellulose into amylose (PNAS, 110: 7182-7187, 2013) and to construct yeast that can phosphorolytically use cellodextrin to produce ethanol. Based on the structure differences in the catalytic loops of CBP and cellodextrin phosphorylase from Clostridium thermocellum (named CtCBP and CtCDP, respectively), CtCBP was mutated to change its substrate specificity. A single-site mutant S497G was identified to exhibit a 5.7-fold higher catalytic efficiency with cellotriose as a substrate in the phosphorolytic reaction compared to the wild type, without any loss of catalytic efficiency on its natural substrate, cellobiose. When the S497G variant was used in the transformation of mixed cellodextrin (cellobiose + cellotriose) to amylose, the amylose yield was significantly increased compared to that of wild-type CtCBP. A structure change in the substrate-binding pocket of the S497G variant accounted for its capacity to accept longer cellodextrins than cellobiose. Taken together, the modified CtCBP, S497G was confirmed to acquire a promising feature favorable to those application scenarios involving cellodextrin's phosphorolysis.

[Heat-inactivated Streptococcus thermophilus MN002 alleviate lipid metabolism of high fat diet-fed induced obese mice through modulating gut microbiota structure and bile acids].

OBJECTIVE: To explore the effects of heat-inactivated Streptococcus thermophilus MN-ZLW-002(MN002) on glucose metabolism, lipid metabolism, gut microbiota and bile acids in high-fat diet fed obese mice. METHODS: Sixty 3-week-old male C57BL/6 mice were randomly divided into control group, high-fat group and intervention group(n=20). After 1 week of adaptive feeding, the control group was fed with normal chow and continued intragastric administration of normal saline for 12 weeks, the high-fat group was fed with high-fat diet and continued intragastric administration of normal saline for 12 weeks, and the intervention group was fed with high-fat diet and continued intragastric of MN002 for 12 weeks. During the experiment, the body weight, food intake, fasting blood glucose content of mice were measured and feces were collected. At the end of the experiment, the oral glucose tolerance of mice was measured and blood, periintestinal fat, peritestosterone fat and perirenal fat samples were collected. The histopathological changes of liver were observed by hematoxylin-eosin staining. Triglyceride, low density lipoprotein, high density lipoprotein and total cholesterol were detected by automatic biochemical analyzer, bile acids content in feces was detected by liquid chromatography-mass spectrometry, gut microbiota structure of mice was analyzed by 16S rDNA sequencing. RESULTS: Compared with high fat group, serum triglyceride, total cholesterol and perirenal fat in intervention group were significantly decreased(P<0.05), the content of fossil cholic acid sulfate in feces was significantly increased, while the content of ursodeoxycholic acid, porcine deoxycholic acid and deoxycholic acid were significantly decreased(P<0.01). Heat inactivation of MN002 could significantly increase the relative abundance of Ruminiclostridium and Alistipes and reduce the relative abundance of Lactobacillus(P<0.01). CONCLUSION: Heat-inactivated Streptococcus thermophilus MN002 can regulate the gut microbiota structure and bile acid composition and content of high-fat diet fed mice, thereby alleviating the lipid metabolic disorders caused by high-fat diet.

Cooperative Ni(Co)-Ru-P Sites Activate Dehydrogenation for Hydrazine Oxidation Assisting Self-powered H2 Production.

Water electrolysis for H2 production is restricted by the sluggish oxygen evolution reaction (OER). Using the thermodynamically more favorable hydrazine oxidation reaction (HzOR) to replace OER has attracted ever-growing attention. Herein, we report a twisted NiCoP nanowire array immobilized with Ru single atoms (Ru1 -NiCoP) as superior bifunctional electrocatalyst toward both HzOR and hydrogen evolution reaction (HER), realizing an ultralow working potential of -60 mV and overpotential of 32 mV for a current density of 10 mA cm-2 , respectively. Inspiringly, two-electrode electrolyzer based on overall hydrazine splitting (OHzS) demonstrates outstanding activity with a record-high current density of 522 mA cm-2 at cell voltage of 0.3 V. DFT calculations elucidate the cooperative Ni(Co)-Ru-P sites in Ru1 -NiCoP optimize H* adsorption, and enhance adsorption of *N2 H2 to significantly lower the energy barrier for hydrazine dehydrogenation. Moreover, a self-powered H2 production system utilizing OHzS device driven by direct hydrazine fuel cell (DHzFC) achieve a satisfactory rate of 24.0 mol h-1 m-2 .

Predicting the clinical outcomes and benefit from letrozole after 5 years of treatment with aromatase inhibitors for early breast cancer: analysis from CCTG MA.17R.

PURPOSE: Women with hormone receptor positive breast cancer may receive 5 years of treatment with aromatase inhibitors but the magnitude of benefit was relatively small. Our goal was to develop a tool for identification of women with limited treatment benefit. METHODS: Regression analyses were applied to women treated by placebo in CCTG MA.17R trial (NCT00754845) to identify important prognostic factors associated with distant recurrence and develop a nomogram for predicting 5-year likelihood of distant recurrence, which was internally validated using bootstrap resampling method. Differential treatment effects between risk categories derived from the nomogram were evaluated among all women enrolled through interaction test between treatment and risk category. RESULTS: A total of 1735 women were included and the final model from 866 women treated by placebo identified the following three factors associate with distant recurrence: tumor size, nodal status, and presence of cardiovascular disease. The nomogram derived from the final model exhibited good discrimination power with a bootstrap-corrected concordance index of 0.71 and, importantly, identified 64% of low risk patients in whom extended treatment has limited benefit. Interaction between treatment and risk category derived from the nomogram was significant (p = 0.04). CONCLUSION: A nomogram with good performance may be used to accurately predict distant recurrence risk and also benefits with extended treatment after 5 years of aromatase inhibitors. Future independent validation of the proposed nomogram is warranted. TRIAL REGISTRATION NUMBER: NCT00754845.

IL-3 Expands Pre-Basophil and Mast Cell Progenitors by Upregulating the IL-3 Receptor Expression.

Basophils and mast cells play a critical role in allergic inflammation and provide protective immunity against certain types of parasitic infections. Expansion of basophils and mast cells to the critical numbers is believed to be an essential step in enabling basophils and mast cells to carry out their protective functions. However, factors that drive basophil and mast cell expansion are still incompletely understood. We tested the roles of cytokines and growth factors IL-3, TSLP, GM-CSF, IL-5, SCF, IL-7, IL-25, and IL-33 in promoting the differentiation of pre-basophil and mast cell progenitors (pre-BMPs)in vitro.We found that while GM-CSF only expanded basophils, IL-3 promoted the differentiation of pre-BMPs into both basophils and mast cells. We found that IL-3 expanded the number of pre-BMPsin vivo. We showed that IL-3 upregulatedIl3ramRNA and protein expression on pre-BMPs, supporting that IL-3 expands pre-BMPs in part by upregulating the IL-3 receptor expression. Although Gata2 mRNA expression was upregulated by IL-3 treatment in pre-BMPs, it is dispensable for IL-3-mediated upregulation of IL-3 receptor expression. Our study reveals a novel mechanism through which IL-3 expands basophil and mast cells.

Antagonistic regulation by the transcription factors C/EBPα and MITF specifies basophil and mast cell fates.

It remains unclear whether basophils and mast cells are derived from a common progenitor. Furthermore, how basophil versus mast cell fate is specified has not been investigated. Here, we have identified a population of granulocyte-macrophage progenitors (GMPs) that were highly enriched in the capacity to differentiate into basophils and mast cells while retaining a limited capacity to differentiate into myeloid cells. We have designated these progenitor cells "pre-basophil and mast cell progenitors" (pre-BMPs). STAT5 signaling was required for the differentiation of pre-BMPs into both basophils and mast cells and was critical for inducing two downstream molecules: C/EBPα and MITF. We have identified C/EBPα as the critical basophil transcription factor for specifying basophil cell fate and MITF as the crucial transcription factor for specifying mast cell fate. C/EBPα and MITF silenced each other's transcription in a directly antagonistic fashion. Our study reveals how basophil and mast cell fate is specified.