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The accumulation of myeloid-derived suppressor cells (MDSCs) has been observed in solid tumors and is correlated with tumor progression; however, the underlying mechanism is still poorly understood. In this study, we identified a mechanism by which tumor cells induce MDSC accumulation and expansion in the bladder cancer (BC) microenvironment via CXCL2/MIF-CXCR2 signaling. Elevated expression of CXCL2 and MIF and an increased number of CD33 + MDSCs were detected in BC tissues, and these increases were significantly associated with advanced disease stage and poor patient prognosis ( P <0.01). A positive association was observed between CXCL2 or MIF expression and the number of tumor-infiltrating CD33 + MDSCs ( P <0.01). Subsequently, we demonstrated that CD45 + CD33 + CD11b + HLA-DR − MDSCs from fresh BC tissues displayed high levels of suppressive molecules, including Arg1, iNOS, ROS, PDL-1 and P-STAT3, and stronger suppression of T-cell proliferation. Interestingly, these CD45 + CD33 + CD11b + HLA-DR − MDSCs exhibited increased CXCR2 expression compared with that in peripheral blood from BC patients or healthy controls ( P <0.05). Chemotaxis assay revealed that bladder cancer cell line J82 induced MDSC migration via CXCL2/MIF-CXCR2 signaling in vitro . Mechanistic studies demonstrated that J82-induced MDSC trafficking and CXCR2 expression were associated with increased phosphorylation of p38, ERK and p65. Conversely, inhibition of the phosphorylation of p38, ERK or p65 decreased J82-induced MDSC trafficking and CXCR2 expression. CXCL2/MIF-stimulated activation of the mitogen-activated protein kinase and nuclear factor kappa B pathways in MDSCs was MyD88 dependent. Overall, our results identify the CXCL2/MIF-CXCR2 axis as an important mediator in MDSC recruitment and as predictors and potential therapeutic targets in BC patients.

Aims/hypothesis There is convincing evidence that endoplasmic reticulum (ER) stress is implicated in the pathogenesis of diabetes and its complications; however, the mechanisms are not fully understood. This study aimed to dissect the role and signalling pathways of activating transcription factor 4 (ATF4) in ER-stress-associated endothelial inflammation and diabetic retinopathy. Methods ER stress and ATF4 activity were manipulated by complementary pharmacological and genetic approaches in cultured retinal endothelial (TR-iBRB) cells. Diabetes was induced by streptozotocin in heterozygous Atf4 knockout and wild-type mice. ER stress markers, inflammatory cytokines and adhesion molecules, activation of the signal transducer and activator of transcription 3 (STAT3) pathway, and retinal vascular permeability were measured. Results High-glucose treatment resulted in rapid induction of ER stress, activation of ATF4, and increased production of inflammatory factors in TR-iBRB cells. Suppressing ER stress or inhibiting ATF4 activity markedly attenuated high-glucose-induced production of intercellular adhesion molecule 1, TNF-α and vascular endothelial growth factor. Conversely, enhancing ER stress or overexpressing Atf4 was sufficient to induce endothelial inflammation, which was, at least in part, through activation of the STAT3 pathway. Furthermore, knockdown of the Stat3 gene or inhibiting STAT3 activity restored ER homeostasis in cells exposed to high glucose and prevented ATF4 activation, suggesting that STAT3 is required for high-glucose-induced ER stress. Finally, we showed that downregulation of Atf4 significantly ameliorated retinal inflammation, STAT3 activation and vascular leakage in a mouse model of type 1 diabetes. Conclusions/interpretation Taken together, our data reveal a pivotal role of ER stress and the ATF4/STAT3 pathway in retinal endothelial inflammation in diabetic retinopathy.

SummaryTo identify the critical genes and pathways that related to OP development in male AS patients, bioinformatic gene analysis and qRT-PCR validation were performed. SBNO2 and VPS13B were identified as the potential target for OP development, which may be valuable for the prevention of OP in male AS patients.IntroductionOsteoporosis (OP) is common in men with ankylosing spondylitis (AS). The specific pathogenesis of OP in AS, however, is still unclear. The present study attempted to identify potential genes associated with the development of OP in males with AS.MethodsGene expression profiles were downloaded from the GSE73754 and GSE35959 datasets from the Gene Expression Omnibus (GEO). Data from OsteoporosAtlas were downloaded as a supplement. Differentially expressed genes (DEGs) were determined with the limma package. The overlapping DEGs between male AS-related genes and OP-related genes were determined. The DEGs were validated by qRT-PCR in the blood samples of males with AS. Weighted gene co-expression network analysis (WGCNA) was utilized to establish a co-expression network to identify the hub genes.ResultsA total of 17 overlapping DEGs were identified; 6 genes in 17 overlapping DEGs were verified as the essential genes in the pathogenesis of OP in male AS by qRT-PCR analysis. After WGCNA, the modules of MEblue (> 0.6) and MEred (> 0.8) were screened out by the correlation analysis and were determined to function mainly in MAPK signaling pathway and osteoclast differentiation. Analysis of the two modules revealed VPS13B and SBNO2 as key genes due to the high degree of correlation. Both genes play an important role in bone metabolism regulation in male AS. Two hub genes MYD88 in MEblue and NCK1 in MEred with high degree of connectivity were selected.ConclusionsGender-specific SBNO2 and VPS13B may be key genes involved in OP in male AS.

To control hepatitis A spread by vaccination, accurate estimation of transmissibility is vital. Regan et al. (2016) proposed a model of hepatitis A virus (HAV) transmission and used least squares to calibrate model to the 1991/1992 HAV outbreak in men who have sex with men (MSM) in Sydney, Australia. Based on the estimate of R 0, they obtained the critical immunity of 70% and showed that when the proportion immune < 70%, there is a definite chance for outbreaks to take place. The immunity level from previous surveys ranges from 32% to 64% after 1996 while no outbreaks in Australian MSMs have been reported since 1996. Further noticing the ill-distributed parameters, we argue that their estimate of R 0 is not accurate. In this study, we revisited their model by Bayesian inference, which has privilege over least squares. We obtained the appropriate posterior distributions of parameters and the estimate of R 0 ranges from 1.38 to 2.89, indicating a critical immunity of 65%. The reduction in critical immunity and outbreak probabilities predicts the absence of outbreaks in Australian MSMs since 1996. Our study shows the importance of using appropriate methods to provide reliable and accurate estimates of the model parameters especially the transmissibility.

A regulator of the protein phosphatase 2A (PP2A), α4, has been implicated in a variety of functions that regulate many cellular processes. To explore the role of α4 in human cell transformation and tumorigenesis, we show that α4 is highly expressed in human cells transformed by chemical carcinogens including benzo( a )pyrene, aflatoxin B 1 , N -methyl- N ′-nitro- N -nitrosoguanidine, nickel sulfate and in several hepatic and lung cancer cell lines. In addition, overexpression of α4 was detected in 87.5% (74/80) of primary hepatocellular carcinomas, 84.0% (21/25) of primary lung cancers and 81.8% (9/11) of primary breast cancers, indicating that α4 is ubiquitously highly expressed in human cancer. Functional studies revealed that elevated α4 expression results in an increase in cell proliferation, promotion of cell survival and decreased PP2A-attributable activity. Importantly, ectopic expression of α4 permits non-transformed human embryonic kidney cells (HEKTER) and L02R cells to form tumors in immunodeficient mice. Furthermore, we show that the highly expressed α4 in transformed cells or human tumors is not regulated by DNA hypomethylation. A microRNA, miR-34b, that suppresses the expression of α4 through specific binding to the 3′-untranslated region of α4 is downregulated in transformed or human lung tumors. Taken together, these observations identify that α4 possesses an oncogenic function. Reduction of PP2A activity due to an enhanced α4–PP2A interaction contributes directly to chemical carcinogen-induced tumorigenesis.

Background Post-operative pneumonia (Pop) following meningioma surgery is the dominant systemic complication which could cause serious threats to patients. It is unclear whether hematological biochemical markers are independently associated with the Pop. This study attempted to perform a more comprehensive study of taking both clinical factors and hematological biomarkers into account to promote the management of patients after meningioma surgery. Methods We collected clinical and hematological parameters of 1156 patients undergoing meningioma resection from January 2009 to January 2013. According to whether the symptoms of pneumonia had manifested,patients were divided into the Pop group and the Non-Pop group. We analyzed the distinctions of clinical factors between the two groups. We successively performed univariate and multivariate regression analysis to identify risk factors independently associated with the Pop. Results 4.4% patients infected with the Pop (51 of 1156). The median age at diagnosis of the Pop patients was significantly older than the Non-Pop group ( p  = 0.002). There were strike distinctions of post-operative hospital stays between two groups, with 21 days and 7 days each ( p  < 0.001). On multivariate analysis, tumor relapse ( p  < 0.001), skull base lesions ( p  = 0.001), intra-operative blood transfusion ( p  = 0.018) and cardiovascular diseases ( p  = 0.001) were linked with increased risk of the Pop following meningioma resection. For hematological biochemical markers, it was the factor of Red blood cell distribution width-standard deviation (RDW-SD) (OR 5.267, 95%CI 1.316, 21.078; p  = 0.019) and Neutrophils lymphocytes ratio (NLR) (OR 2.081, 95%CI 1.063, 4.067; p  = 0.033) that could appreciably predict the Pop. Conclusions Apart from tumor recurrence, localizations, intra-operative blood transfusion and cardiovascular diseases are independent risk factors for the Pop. We initially found hematological RDW-SD and NLR are also important predictors.

Despite physiological importance of aldonic sugar acids for living organisms, little is known about metabolic pathways of these compounds. Here, we investigated the functional diversity of homologs of L-threonic acid dehydrogenase (ThrDH; UniProt ID: Q0KBC7), an enzyme composed of two NAD-binding domains (PF14833 and PF03446). Ten ThrDH homologs with different genomic context were studied; seven new enzymatic activities were identified, such as (R)-pantoate dehydrogenase, L-altronic acid dehydrogenase, 6-deoxy-L-talonate dehydrogenase, L-idonic acid dehydrogenase, D-xylonic acid dehydrogenase, D-gluconic acid dehydrogenase, and 2-hydroxy-3-oxopantoate reductase activities. Two associated metabolic pathways were identified: L-idonic acid dehydrogenase was found to be involved in the degradation of L-idonic acid through oxidation/decarboxylation in Agrobacterium radiobacter K84, while 2-hydroxy-3-oxopantoate reductase was found to participate in D-glucarate catabolism through dehydration/cleavage in Ralstonia metallidurans CH34.

Chitosanase plays a pivotal role in the production of chitooligosaccharide. Nevertheless, there is untapped potential for enhancing both its catalytic efficiency and thermostability, which could significantly bolster its therapeutic and biotechnological applications. In this study, two computer-aided protein design methods, namely Fireprot and PROSS, were utilized to pinpoint 6 single Bacillus subtilis chitosanase BsCsn46A mutants (S126A, D191A, K70A, L159I, K104P, and A129L) as well as 4 multiple mutants (K70A/S126A, K70A/S126A/K104P, K70A/S126A/L159I, and K70A/S126A/K104P/L159). The wild-type (WT) and all 10 BsCsn46A mutants displayed robust adaptability across a broad pH range, exhibiting peak activity within the pH spectrum of 5.5 to 9.5. The results demonstrated that, compared to the WT, 9 out of 10 mutants exhibited significantly heightened chitosanase activity, with the sole exception being the D191A mutant, which displayed activity levels nearly identical to the WT. Notably, the A129L displayed an impressive 20% increase in the enzyme activity at elevated temperatures, specifically in the range of 55–80°C. Assessing protein stability, results indicated that all samples maintained stability when incubated at 30°C for 1 h. However, when subjected to a higher temperature of 40°C for 1 h, only the A129L mutant retained stability, which persisted even after an extended incubation period of 3 h at 40°C. Furthermore, a thermal stability analysis revealed noteworthy differences between the WT and the mutants. The WT chitosanase activity diminished by 50% after brief 30-min incubation at 50°C, whereas the K70A/S126A, K70A/S126A/K104P, and A129L mutants maintained 50% of their activity for approximately 2 h under the same conditions. In summary, the study provides valuable insights into the thermostability and catalytic activity of chitosanase, highlighting promising candidates for industrial chitosanase applications.

Wheat powdery mildew (Bgt), a fungal seeding disease, is a threat to wheat agriculture worldwide. In this study, iron shell wheat (Triticum aestivum ssp. yunnanense King) was used as the research material. Extensive targeted metabolomic analysis was conducted on the leaves of the susceptible strain iron shell wheat 1 (DiKe 1) and the normal resistant strain Zhenkang iron shell wheat (Yunmai 0030). Furthermore, the dynamic physiological changes in metabolite levels between the two strains were assessed. Significant differences were identified in tryptophan and pyrimidine metabolism as well as isoquinoline alkaloid biosynthesis. The main metabolites were phenolic acids, flavonoid carboglycosides, indole alkaloids, phenolic amines, amino acids, and their derivatives. The defense response to powdery mildew in the iron shell wheat was dominated by tryptophan metabolism. The importance of L-dopa and tyramine in powdery mildew resistance provides new insights into the relevant mechanisms and can help identify antigens for use in the breeding of powdery-mildew-resistant wheat varieties.

The Yellow Sea, surrounded by East China and the Korea Peninsula, is a potentially important receptor for anthropogenic mercury (Hg) emissions from East Asia. However, there is little documentation about the distribution and cycle of Hg in this marine system. During the cruise covering the Yellow Sea in July 2010, gaseous elemental mercury (GEM or Hg(0)) in the atmosphere, total Hg (THg), reactive Hg (RHg) and dissolved gaseous mercury (DGM, largely Hg(0)) in the waters were measured aboard the R/V Kexue III. The mean (±SD) concentration of GEM over the entire cruise was 2.61 ± 0.50 ng m−3 (range: 1.68 to 4.34 ng m−3), which were generally higher than other open oceans. The spatial distribution of GEM generally reflected a clear gradient with high levels near the coast of East China and low levels in open waters, suggesting the significant atmospheric Hg outflow from East China. The mean concentration of THg in the surface waters was 1.69 ± 0.35 ng l−1 and the RHg accounted for a considerable fraction of THg (RHg: 1.08 ± 0.28 ng l−1, %RHg/THg = 63.9%). The mean concentration of DGM in the surface waters was 63.9 ± 13.7 pg l−1 and always suggested the supersaturation of Hg(0) in the surface waters with respect to Hg(0) in the atmosphere (the degree of saturation: 7.8 ± 2.3 with a range of 3.6–14.0). The mean Hg(0) flux at the air-sea interface was estimated to be 18.3 ± 11.8 ng m−2 h−1 based on a two-layer exchange model. The high wind speed and DGM levels induced the extremely high Hg(0) emission rates. Measurements at three stations showed no clear vertical patterns of DGM, RHg and THg in the water column. Overall, the elevated Hg levels in the Yellow Sea compared with other open oceans suggested that the human activity has influenced the oceanic Hg cycle downwind of East Asia.