Comprehensive analyses for the coagulation and macrophage-related genes to reveal their joint roles in the prognosis and immunotherapy of lung adenocarcinoma patients

PurposeThis study aims to explore novel biomarkers related to the coagulation process and tumor-associated macrophage (TAM) infiltration in lung adenocarcinoma (LUAD).MethodsThe macrophage M2-related genes were obtained by Weighted Gene Co-expression Network Analysis (WGCNA) in bulk RNA-seq data, while the TAM marker genes were identified by analyzing the scRNA-seq data, and the coagulation-associated genes were obtained from MSigDB and KEGG databases. Survival analysis was performed for the intersectional genes. A risk score model was subsequently constructed based on the survival-related genes for prognosis prediction and validated in external datasets.ResultsIn total, 33 coagulation and macrophage-related (COMAR) genes were obtained, 19 of which were selected for the risk score model construction. Finally, 10 survival-associated genes (APOE, ARRB2, C1QB, F13A1, FCGR2A, FYN, ITGB2, MMP9, OLR1, and VSIG4) were involved in the COMAR risk score model. According to the risk score, patients were equally divided into low- and high-risk groups, and the prognosis of patients in the high-risk group was significantly worse than that in the low-risk group. The ROC curve indicated that the risk score model had high sensitivity and specificity, which was validated in multiple external datasets. Moreover, the model also had high efficacy in predicting the clinical outcomes of LUAD patients who received anti-PD-1/PD-L1 immunotherapy.ConclusionThe COMAR risk score model constructed in this study has excellent predictive value for the prognosis and immunotherapeutic clinical outcomes of patients with LUAD, which provides potential biomarkers for the treatment and prognostic prediction

Resolving Fine-Scale Surface Features on Polar Sea Ice: A First Assessment of UAS Photogrammetry Without Ground Control

Mapping landfast sea ice at a fine spatial scale is not only meaningful for geophysical study, but is also of benefit for providing information about human activities upon it. The combination of unmanned aerial systems (UAS) with structure from motion (SfM) methods have already revolutionized the current close-range Earth observation paradigm. To test their feasibility in characterizing the properties and dynamics of fast ice, three flights were carried out in the 2016–2017 austral summer during the 33rd Chinese National Antarctic Expedition (CHINARE), focusing on the area of the Prydz Bay in East Antarctica. Three-dimensional models and orthomosaics from three sorties were constructed from a total of 205 photos using Agisoft PhotoScan software. Logistical challenges presented by the terrain precluded the deployment of a dedicated ground control network; however, it was still possible to indirectly assess the performance of the photogrammetric products through an analysis of the statistics of the matching network, bundle adjustment, and Monte-Carlo simulation. Our results show that the matching networks are quite strong, given a sufficient number of feature points (mostly > 20,000) or valid matches (mostly > 1000). The largest contribution to the total error using our direct georeferencing approach is attributed to inaccuracies in the onboard position and orientation system (POS) records, especially in the vehicle height and yaw angle. On one hand, the 3D precision map reveals that planimetric precision is usually about one-third of the vertical estimate (typically 20 cm in the network centre). On the other hand, shape-only errors account for less than 5% for the X and Y dimensions and 20% for the Z dimension. To further illustrate the UAS’s capability, six representative surface features are selected and interpreted by sea ice experts. Finally, we offer pragmatic suggestions and guidelines for planning future UAS-SfM surveys without the use of ground control. The work represents a pioneering attempt to comprehensively assess UAS-SfM survey capability in fast ice environments, and could serve as a reference for future improvements

Biases and improvements of the boreal winter–spring equatorial undercurrent in the Indian Ocean in the CMIP5 and CMIP6 models

We assessed the performance of state-of-the-art coupled models in reproducing the equatorial undercurrent (EUC) in the Indian Ocean based on the outputs of the Coupled Model Intercomparison Project Phase 6 (CMIP6) models and compared with the Phase 5 (CMIP5) models. Our results showed that the CMIP6 models reproduced the boreal winter–spring Indian Ocean EUC more realistically than the CMIP5 models, although both generations of models underestimated the strength of the Indian Ocean EUC compared with the observations. This underestimation of the Indian Ocean EUC can be attributed to the excessively strong and westward-extended cold tongue in the equatorial Pacific. In the CMIP models, a stronger winter-mean cold tongue favors a stronger zonal sea surface temperature gradient, which forces a strong easterly wind bias over the equatorial western Pacific. This, in turn, contributes to an acceleration of the Walker circulation. This enhanced Walker circulation over the Indo-Pacific Ocean directly causes a lower level westerly wind bias over the equatorial Indian Ocean and drives a shallow west–deep east thermocline tilt bias, ultimately leading to an excessively weak EUC in the Indian Ocean via wind-induced thermocline processes. Compared with the CMIP5 models, the overall improvement in the strength of the winter–spring Indian Ocean EUC in the CMIP6 models can be traced back to the improvement in the degree of the strong and westward-extended cold tongue bias. Our results suggest that efforts should be made to reduce the bias in the mean-state equatorial Pacific sea surface temperature to further improve the simulation and projection of the atmospheric and oceanic circulations in the Indian Ocean

P14AS upregulates gene expression in the CDKN2A/2B locus through competitive binding to PcG protein CBX7

Background: It is well known that P16INK4A, P14ARF, P15INK4B mRNAs, and ANRIL lncRNA are transcribed from the CDKN2A/2B locus. LncRNA P14AS is a lncRNA transcribed from antisense strand of P14ARF promoter to intron-1. Our previous study showed that P14AS could upregulate the expression level of ANRIL and P16INK4A and promote the proliferation of cancer cells. Because polycomb group protein CBX7 could repress P16INK4A expression and bind ANRIL, we wonder whether the P14AS-upregulated ANRIL and P16INK4A expression is mediated with CBX7.Results: In this study, we found that the upregulation of P16INK4A, P14ARF, P15INK4B and ANRIL expression was induced by P14AS overexpression only in HEK293T and HCT116 cells with active endogenous CBX7 expression, but not in MGC803 and HepG2 cells with weak CBX7 expression. Further studies showed that the stable shRNA-knockdown of CBX7 expression abolished the P14AS-induced upregulation of these P14AS target genes in HEK293T and HCT116 cells whereas enforced CBX7 overexpression enabled P14AS to upregulate expression of these target genes in MGC803 and HepG2 cells. Moreover, a significant association between the expression levels of P14AS and its target genes were observed only in human colon cancer tissue samples with high level of CBX7 expression (n = 38, p < 0.05), but not in samples (n = 37) with low level of CBX7 expression, nor in paired surgical margin tissues. In addition, the results of RNA immunoprecipitation (RIP)- and chromatin immunoprecipitation (ChIP)-PCR analyses revealed that lncRNA P14AS could competitively bind to CBX7 protein which prevented the bindings of CBX7 to both lncRNA ANRIL and the promoters of P16INK4A, P14ARF and P15INK4B genes. The amounts of repressive histone modification H3K9m3 was also significantly decreased at the promoters of these genes by P14AS in CBX7 actively expressing cells.Conclusions: CBX7 expression is essential for P14AS to upregulate the expression of P16INK4A, P14ARF, P15INK4B and ANRIL genes in the CDKN2A/2Blocus. P14AS may upregulate these genes’ expression through competitively blocking CBX7-binding to ANRIL lncRNA and target gene promoters

Prevalence of A2143G mutation of H. pylori-23S rRNA in Chinese subjects with and without clarithromycin use history

<p>Abstract</p> <p>Background</p> <p>A2143G mutation of <it>23S rRNA </it>gene of <it>H. pylori </it>results in clarithromycin (CLR) resistance. To investigate the prevalence of the CLR resistance-related A2143G mutation of the <it>H. pylori</it>-specific <it>23S rRNA </it>gene in Chinese subjects with and without CLR use history, 307 subjects received the treatment with amoxicillin and omeprazole (OA) and 310 subjects received a placebo in 1995, and 153 subjects received a triple therapy with OA and CLR (OAC) in 2000. DNA was extracted from fasting gastric juice at the end of the intervention trial in 2003. <it>H. pylori </it>infection was determined by <it>H. pylori</it>-specific <it>23S rRNA </it>PCR, ELISA, and¹³C-urea breath test assays. Mutations of the <it>23S rRNA </it>gene were detected by RFLP assays.</p> <p>Results</p> <p>The presence of <it>23S rRNA </it>due to <it>H. pylori </it>infection in the OA group remained lower than that in the placebo group 7.3 yrs after OA-therapy [51.1% (157/307) vs. 83.9% (260/310), p = 0.0000]. In the OAC group, the <it>23S rRNA </it>detection rate was 26.8% (41/153) three yrs after OAC-treatment. The A2143G mutation rate among the <it>23S rRNA</it>-positive subjects in the OAC group [31.7% (13/41)] was significantly higher than that in the OA group [10.2% (16/157)] and the placebo group [13.8% (36/260)]. The frequency of the AAGGG → CTTCA (2222–2226) and AACC → GAAG (2081–2084) sequence alterations in the OAC group was also significantly higher than those in the OA group and the placebo group.</p> <p>Conclusion</p> <p>Primary prevalence of the A2143G mutation was 10~14% among Chinese population without history of CLR therapy. Administration of CLR to eliminate <it>H. pylori </it>infection increased the prevalence of the A2143G mutation in Chinese subjects (32%) significantly.</p

Meteorin-like/Metrnl, a novel secreted protein implicated in inflammation, immunology, and metabolism: A comprehensive review of preclinical and clinical studies

Meteorin-like, also known as Metrnl, Meteorin-β, Subfatin, and Cometin, is a novel secreted protein exerting pleiotropic effects on inflammation, immunology, and metabolism. Earlier research on this hormone focused on regulating energy expenditure and glucose homeostasis. Consequently, several studies attempted to characterize the molecule mechanism of Metrnl in glucose metabolism and obesity-related disorders but reported contradictory clinical results. Recent studies gradually noticed its multiple protective functions in inflammatory immune regulations and cardiometabolic diseases, such as inducing macrophage activation, angiogenesis, tissue remodeling, bone formation, and preventing dyslipidemias. A comprehensive understanding of this novel protein is essential to identify its significance as a potential therapeutic drug or a biomarker of certain diseases. In this review, we present the current knowledge on the physiology of Metrnl and its roles in inflammation, immunology, and metabolism, including animal/cell interventional preclinical studies and human clinical studies. We also describe controversies regarding the data of circulation Metrnl in different disease states to determine its clinical application better

The first comprehensive study of a giant nebula around a radio-quiet quasar in the z<1z < 1 Universe

We present the first comprehensive study of a giant, $\approx \! \! 70$ kpc-scale nebula around a radio-quiet quasar at $z<1$. The analysis is based on deep integral field spectroscopy with MUSE of the field of HE$\,$0238$-$1904, a luminous quasar at $z=0.6282$. The nebula emits strongly in $\mathrm{[O \, II]}$, $\rm H \beta$, and $\mathrm{[O \, III]}$, and the quasar resides in an unusually overdense environment for a radio-quiet system. The environment likely consists of two groups which may be merging, and in total have an estimated dynamical mass of $M_{\rm dyn}\approx 4\times 10^{13}$ to $10^{14}\ {\rm M_\odot}$. The nebula exhibits largely quiescent kinematics and irregular morphology. The nebula may arise primarily through interaction-related stripping of circumgalactic and interstellar medium (CGM/ISM) of group members, with some potential contributions from quasar outflows. The simultaneous presence of the giant nebula and a radio-quiet quasar in a rich environment suggests a correlation between such circum-quasar nebulae and environmental effects. This possibility can be tested with larger samples. The upper limits on the electron number density implied by the$\mathrm{[O \, II]}$doublet ratio range from$\log(n_{\rm e, \, [O \, II]} / \mathrm{cm^{-3}}) < 1.2$to$2.8$. However, assuming a constant quasar luminosity and negligible projection effects, the densities implied from the measured line ratios between different ions (e.g.,$\mathrm{[O\,II]}$,$\mathrm{[O\,III]}$, and$\mathrm{[Ne\,V]}$) and photoionization simulations are often$10{-}400$times larger. This large discrepancy can be explained by quasar variability on a timescale of$\approx 10^4{-}10^5$ years.Comment: 19 pages, 9 figures, 3 tables; Submitted to MNRA

Microbial metabolites indole derivatives sensitize mice to D-GalN/LPS induced-acute liver failure via the Tlr2/NF-κB pathway

IntroductionAcute liver failure (ALF) is a clinical condition with many causes, fast progression, and a poor prognosis. Previous research has indicated that microbial factors have a role in ALF, but a clear picture has yet to emerge.MethodsTo investigate the specific involvement of microbial metabolites in ALF development, we pretreated D-GalN/LPS-induced ALF mice with indole derivatives, an influential class of gut microbial metabolites.ResultsContrary to their typical role as anti-inflammatory agents in the host, indole-3-acetic acid (IAA), indole-3-lactic acid (ILA), and indolepropionic acid (IPA) gavage sensitize mice to D-GalN/LPS-induced-ALF with a rapid rise in serum transaminases and histologic lesion. For a clearer picture, we performed comprehensive analysis for the IAA therapy. IAA markedly amplified inflammatory response and cellular damage. The transcriptome analysis indicated the participation of the TNF-α/NF-κB signaling pathway. The structure of gut microbiota in ileum and the expression of Toll-like receptor 2 (Tlr2) in the liver were also significantly changed.DiscussionIn conclusion, IAA pretreatment can exacerbate D-GalN/LPS-induced ALF via probable Tlr2/NF-κB pathway involvement and ileac dysbiosis characterized by enriched gram-positive genus with potential pathogenesis. Microbial metabolites IAA may aggravate individual susceptibility to D-GalN/LPS-induced ALF. Further investigation of the underlying mechanism is needed, and intervention with indole derivatives and related commensal species should be undertaken with caution