Mycobacterial CpsA activates type I IFN signaling in macrophages via cGAS-mediated pathway.

Type I interferon (IFN) production is crucial in tuberculosis pathogenesis, yet the bacterial factors initiating this process are incompletely understood. CpsA, protein of Mycobacterium marinum and Mycobacterium tuberculosis, plays a key role in maintaining bacterial virulence and inhibiting host cell LC3-associated phagocytosis. By utilizing CpsA full deletion mutant studies, we re-verified its essential role in infection-induced pathology and revealed its new role in type I IFN expression. CpsA deficiency hindered IFN production in infected macrophages in vitro as well as zebrafish and mice in vivo. This effect was linked to the cGAS-TBK1-IRF3 pathway, as evidenced by decreased TBK1 and IRF3 phosphorylation in CpsA-deficient bacterial strain-infected macrophages. Moreover, we further show that CpsA deficiency cause decreased cytosolic DNA levels, correlating with impaired phagosomal membrane rupture. Our findings reveal a new function of mycobacterial CpsA in type I IFN production and offer insight into the molecular mechanisms underlying mycobacterial infection pathology.

Genetically encoded transcriptional plasticity underlies stress adaptation in Mycobacterium tuberculosis.

Transcriptional regulation is a critical adaptive mechanism that allows bacteria to respond to changing environments, yet the concept of transcriptional plasticity (TP) - the variability of gene expression in response to environmental changes - remains largely unexplored. In this study, we investigate the genome-wide TP profiles of Mycobacterium tuberculosis (Mtb) genes by analyzing 894 RNA sequencing samples derived from 73 different environmental conditions. Our data reveal that Mtb genes exhibit significant TP variation that correlates with gene function and gene essentiality. We also find that critical genetic features, such as gene length, GC content, and operon size independently impose constraints on TP, beyond trans-regulation. By extending our analysis to include two other Mycobacterium species -- M. smegmatis and M. abscessus -- we demonstrate a striking conservation of the TP landscape. This study provides a comprehensive understanding of the TP exhibited by mycobacteria genes, shedding light on this significant, yet understudied, genetic feature encoded in bacterial genomes.

In vivo RNA interactome profiling reveals 3'UTR-processed small RNA targeting a central regulatory hub.

Small noncoding RNAs (sRNAs) are crucial regulators of gene expression in bacteria. Acting in concert with major RNA chaperones such as Hfq or ProQ, sRNAs base-pair with multiple target mRNAs and form large RNA-RNA interaction networks. To systematically investigate the RNA-RNA interactome in living cells, we have developed a streamlined in vivo approach iRIL-seq (intracellular RIL-seq). This generic approach is highly robust, illustrating the dynamic sRNA interactomes in Salmonella enterica across multiple stages of growth. We have identified the OmpD porin mRNA as a central regulatory hub that is targeted by a dozen sRNAs, including FadZ cleaved from the conserved 3'UTR of fadBA mRNA. Both ompD and FadZ are activated by CRP, constituting a type I incoherent feed-forward loop in the fatty acid metabolism pathway. Altogether, we have established an approach to profile RNA-RNA interactomes in live cells, highlighting the complexity of RNA regulatory hubs and RNA networks.

Predictors of Long-Term Rebleeding Risk in Cirrhotic Patients Undergoing Esophagogastric Devascularization and Splenectomy: Impact of Portal Vein Thrombosis and Hemoglobin Levels.

BACKGROUND Esophagogastric devascularization and splenectomy (EGDS) is widely used to treat patients with portal hypertension in China. This study aimed to determine risk factors that increase risk of rebleeding after EGDS and evaluate the effect of portal vein thrombosis (PVT) on rebleeding rates after EGDS. MATERIAL AND METHODS Clinical data of patients with cirrhosis (n=138) who underwent EGDS between December 2010 and January 2016 were retrospectively analyzed. Patients were assigned to rebleeding or non-rebleeding groups and followed up. Univariate and multivariate Cox regression analyses identified the independent predictors of 3-year and 5-year rebleeding. RESULTS A total of 138 consecutive patients who underwent EGDS and met the inclusion criteria were enrolled. Total bilirubin (HR: 2.392, 95% CI 1.032-5.545, P=0.042) and PVT (HR: 3.345, 95% CI 1.477-7.573, P=0.004) predicted 3-year rebleeding during univariate analysis. Multivariate analysis revealed that PVT (HR: 3.967, 95% CI 1.742-9.035, P=0.001) was an independent predictor. Hemoglobin >87.5 g/L (HR: 3.104, 95% CI 1.283-7.510, P=0.012) and PVT (HR: 2.349, 95% CI 1.231-4.483, P=0.010) were predictors of 5-year rebleeding during multivariate analysis. Albumin >37.5 g/L was an independent predictor of rebleeding in patients with PVT at 3 and 5 years (HR: 3.964, 95% CI 1.301-9.883, P=0.008; HR: 3.193, 95% CI 1.275-7.997, P=0.013, respectively). CONCLUSIONS PVT is associated with increased 3-year and 5-year rebleeding rates after EGDS but not at 10 years. Also, hemoglobin >87.5 g/L predicted rebleeding at 5 years. Albumin has huge prospects as a predictor of rebleeding at 3 and 5 years in patients with PVT.

Genetically encoded transcriptional plasticity underlies stress adaptation in Mycobacterium tuberculosis.

Transcriptional regulation is a critical adaptive mechanism that allows bacteria to respond to changing environments, yet the concept of transcriptional plasticity (TP) remains largely unexplored. In this study, we investigate the genome-wide TP profiles of Mycobacterium tuberculosis (Mtb) genes by analyzing 894 RNA sequencing samples derived from 73 different environmental conditions. Our data reveal that Mtb genes exhibit significant TP variation that correlates with gene function and gene essentiality. We also found that critical genetic features, such as gene length, GC content, and operon size independently impose constraints on TP, beyond trans-regulation. By extending our analysis to include two other Mycobacterium species -- M. smegmatis and M. abscessus -- we demonstrate a striking conservation of the TP landscape. This study provides a comprehensive understanding of the TP exhibited by mycobacteria genes, shedding light on this significant, yet understudied, genetic feature encoded in bacterial genomes.

Genetically encoded transcriptional plasticity underlies stress adaptation in Mycobacterium tuberculosis.

Transcriptional regulation is a critical adaptive mechanism that allows bacteria to respond to changing environments, yet the concept of transcriptional plasticity (TP) remains largely unexplored. In this study, we investigate the genome-wide TP profiles of Mycobacterium tuberculosis (Mtb) genes by analyzing 894 RNA sequencing samples derived from 73 different environmental conditions. Our data reveal that Mtb genes exhibit significant TP variation that correlates with gene function and gene essentiality. We also found that critical genetic features, such as gene length, GC content, and operon size independently impose constraints on TP, beyond trans-regulation. By extending our analysis to include two other Mycobacterium species -- M. smegmatis and M. abscessus -- we demonstrate a striking conservation of the TP landscape. This study provides a comprehensive understanding of the TP exhibited by mycobacteria genes, shedding light on this significant, yet understudied, genetic feature encoded in bacterial genomes.

Transcriptomic Analysis of Mycobacterial Infected Macrophages Reveals a High MOI Specific Type I IFN Signaling.

Macrophage (MΦ) infection models are important tools for studying host-mycobacterial interactions. Although the multiplicity of infection (MOI) is an important experimental variable, the selection of MOI in mycobacterial infection experiments is largely empirical, without reference to solid experimental data. To provide relevant data, we used RNA-seq to analyze the gene expression profiles of MΦs 4 or 24 h after infection with Mycobacterium marinum (M. m) at MOIs ranging from 0.1 to 50. Analysis of differentially expressed genes (DEGs) showed that different MOIs are linked to distinct transcriptomic changes and only 10% of DEGs were shared by MΦ infected at all MOIs. KEGG pathway enrichment analysis revealed that type I interferon (IFN)-related pathways were inoculant dose-dependent and enriched only at high MOIs, whereas TNF pathways were inoculant dose-independent and enriched at all MOIs. Protein-protein interaction (PPI) network alignment showed that different MOIs had distinct key node genes. By fluorescence-activated cell sorting and follow-up RT-PCR analysis, we could separate infected MΦs from uninfected MΦs and found phagocytosis of mycobacteria to be the determinant factor for type I IFN production. The distinct transcriptional regulation of RAW264.7 MΦ genes at different MOIs was also seen with Mycobacterium tuberculosis (M.tb) infections and primary MΦ infection models. In summary, transcriptional profiling of mycobacterial infected MΦs revealed that different MOIs activate distinct immune pathways and the type I IFN pathway is activated only at high MOIs. This study should provide guidance for selecting the MOI most appropriate for different research questions.

Drug Degradation Caused by mce3R Mutations Confers Contezolid (MRX-I) Resistance in Mycobacterium tuberculosis.

Contezolid (MRX-I), a safer antibiotic of the oxazolidinone class, is a promising new antibiotic with potent activity against Mycobacterium tuberculosis (MTB) both in vitro and in vivo. To identify resistance mechanisms of contezolid in MTB, we isolated several in vitro spontaneous contezolid-resistant MTB mutants, which exhibited 16-fold increases in the MIC of contezolid compared with the parent strain but were still unexpectedly susceptible to linezolid. Whole-genome sequencing revealed that most of the contezolid-resistant mutants bore mutations in the mce3R gene, which encodes a transcriptional repressor. The mutations in mce3R led to markedly increased expression of a monooxygenase encoding gene Rv1936. We then characterized Rv1936 as a putative flavin-dependent monooxygenase that catalyzes the degradation of contezolid into its inactive 2,3-dihydropyridin-4-one (DHPO) ring-opened metabolites, thereby conferring drug resistance. While contezolid is an attractive drug candidate with potent antimycobacterial activity and low toxicity, the occurrence of mutations in Mce3R should be considered when designing combination therapy using contezolid for treating tuberculosis.

Microvesicles: the functional mediators in sorafenib resistance.

Overcoming drug resistance in cancer therapies remains challenging, and the tumor microenvironment plays an important part in it. Microvesicles (MVs) are functional natural carriers of cellular information, participate in intercellular communication, and dynamically regulate the tumor microenvironment. They contribute to drug resistance by transferring functional molecules between cells. Conversely, due to their specific cell or tissue targeting ability, MVs are considered as carriers for therapeutic molecules to reverse drug resistance. Thus, in this mini-review, we aim to highlight the crucial role of MVs in cell-to-cell communication and therefore their diverse impact mainly on liver cancer progression and treatment. In addition, we summarize the possible mechanisms for sorafenib resistance (one of the main hurdles in hepatocellular carcinoma treatments) and recent advances in using MVs to reverse sorafenib resistance in liver cancer therapies. Identifying the functional role of MVs in cancer therapy might provide a new aspect for developing precise novel therapeutics in the future.

Modern Beijing sublineage of Mycobacterium tuberculosis shift macrophage into a hyperinflammatory status.

The high prevalence of the modern Beijing sublineage of Mycobacterium tuberculosis may be related to increased virulence, although the responsible mechanisms remain poorly understood. We previously described enhanced triacylglycerol accumulation in modern Beijing strains. Here we show that modern Beijing strains grow faster in vitro and trigger a vigorous immune response and pronounced macrophage infiltration. Transcriptomic analysis of bone marrow derived macrophages infected with modern Beijing lineage strains revealed a significant enrichment of infection, cholesterol homeostasis and amino acid metabolic pathways. The upregulation of proinflammatory / bactericidal cytokines was confirmed by RT-PCR analysis, which is also in consistent with the reduced bacterial burden in modern strains infected macrophages. These results suggest that modern Beijing strains elicit a hyperinflammatory response which might indicate a stronger virulence and contribute to their extensive global prevalence.

A radiomics-based model on non-contrast CT for predicting cirrhosis: make the most of image data.

BACKGROUND: To establish and validate a radiomics-based model for predicting liver cirrhosis in patients with hepatitis B virus (HBV) by using non-contrast computed tomography (CT). METHODS: This retrospective study developed a radiomics-based model in a training cohort of 144 HBV-infected patients. Radiomic features were extracted from abdominal non-contrast CT scans. Features selection was performed with the least absolute shrinkage and operator (LASSO) method based on highly reproducible features. Support vector machine (SVM) was adopted to build a radiomics signature. Multivariate logistic regression analysis was used to establish a radiomics-based nomogram that integrated radiomics signature and other independent clinical predictors. Performance of models was evaluated through discrimination ability, calibration and clinical benefits. An internal validation was conducted in 150 consecutive patients. RESULTS: The radiomics signature comprised 25 cirrhosis-related features and showed significant differences between cirrhosis and non-cirrhosis cohorts (P < 0.001). A radiomics-based nomogram that integrates radiomics signature, alanine transaminase, aspartate aminotransferase, globulin and international normalized ratio showed great calibration and discrimination ability in the training cohort (area under the curve [AUC]: 0.915) and the validation cohort (AUC: 0.872). Decision curve analysis confirmed the most clinical benefits can be provided by the nomogram compared with other methods. CONCLUSIONS: Our developed radiomics-based nomogram can successfully diagnose the status of cirrhosis in HBV-infected patients, that may help clinical decision-making.

Root and nitrate-N distribution and optimization of N input in winter wheat.

Scientific management of nitrogen (N) fertilizer has a significant effect on yield while also reducing the environmental risks. In this study, we conducted field experiments over three years at two different sites (Zhengzhou and Shangshui) in Henan Province, China, using different N application rates (0, 90,180, 270, and 360 kg ha-1) to determine the relationships between soil N supply and N demand in winter wheat (Triticum aestivum L.). Optimal N input was then determined. Both sites showed the same trend. Namely, aboveground N uptake and soil nitrate N (NO3--N) increased with increasing N, while NO3--N decreased with increasing soil depth, gradually moving downwards with growth. A significant correlation (p < 0.001) between increasing aboveground N uptake and increasing NO3--N was also observed under N application, with the best relationships occurring in the 20-60 cm layer during jointing-anthesis (R2 = 0.402-0.431) and the 20-80 cm layer at maturity (R2 = 0.474). Root weight density showed the same spatial-temporal characteristics as NO3--N, following a unimodal trend with increasing N, and peaking at 90 kg ha-1. The root weight density was mainly distributed in the 0-60 cm layer (above 80%), with the 20-60 cm layer accounting for 30% of the total root system. In this layer, the root weight density was also significantly positively correlated with aboveground N uptake. Wheat yield reached saturation under high N (>270 kg ha-1), with a sharp decrease in N use efficiency (NUE) and linear increase in residual NO3--N. To balance yield and the risk of environmental pollution in the experimental area, an N application rate of 180-270 kg ha-1 is recommended under sufficient irrigation, thereby supporting a well-developed root system while ensuring balance between N supply and demand.

Spencerozyma acididurans sp. nov., an acid-tolerant basidiomycetous yeast species isolated from acid mine drainage.

Strain SYSU-17, representing a novel acid-tolerant yeast species which can grow at pH 2.0 weakly, was isolated from acid mine drainage collected in a tailing impoundment of the Fankou Lead/Zinc Mine, Guangdong Province, PR China. Phylogenetic analysis of strain SYSU-17 based on the internal transcribed spacer (ITS) region and the D1/D2 domains of the large subunit ribosomal RNA (LSU rRNA) gene suggested that strain SYSU-17 was a novel species belonging to the genus Spencerozyma (class Microbotryomycetes, subphylum Pucciniomycotina). It differed from the type strain of the closest related species, Spencerozyma crocea CBS 2029T, by 0.7 % sequence divergence (three gaps and one nucleotide substitution out of 594 bp) in the D1/D2 domains of the LSU rRNA gene and 7.6 % sequence divergence (32 gaps and 22 nucleotide substitutions out of 714 bp) in the ITS region. In contrast to the physiological properties of S. crocea, the novel yeast species was unable to assimilate galactose, d-ribose, xylitol, succinate, d-xylose, ethanol, nitrate and nitrite. The name Spencerozyma acididurans sp. nov. is proposed and SYSU-17 is designated as the holotype.

[Nitrogen and Phosphorous Adsorption Characteristics of Suspended Solids Input into a Drinking Water Reservoir via Typhoon Heavy Rainfall].

During typhoon "Mujigae" in October 2015, water samples and surface sediments were collected from Gaozhou Reservoir, a drinking water reservoir, for simulation and analysis of the kinetics of suspended solids adsorption to nitrogen and phosphorus and the adsorption isotherms of suspended solids with different particle sizes and different concentrations. The results showed no obvious nitrogen adsorption of suspended solids of Gaozhou Reservoir. However, the adsorption effect to phosphorus by suspended solids was significant and the equilibrium time of phosphorus adsorption was 10 hours. The adsorption capacity of phosphorus increased with the decrease of sediment particle size when particle sizes were less than 0.25 mm, whereas it increased with the increase of suspended solids concentration when the concentration was in the range of 0.2-2.0 kg·m-3. The adsorption isotherm of suspended solids to phosphorus conformed to the Langmuir and Freundlich models, and the maximum adsorption capacity increased with the decrease of suspended solids particle sizes, which increased with the increase of suspended solids concentrations. The maximum adsorption capacity of suspended solids to phosphorus was 0.073-1.776 mg·g-1. These results indicated that the increase of suspended solids concentration due to the heavy rainfall of the typhoon promoted the adsorption of suspended solids to phosphorus, which reduced eutrophication in Gaozhou Reservoir.

Cochlear implantation in patients with canal wall down mastoidectomy cavities.

BACKGROUND: Safe cochlear implantation (CI) is challenging in patients with a canal wall down (CWD) mastoidectomy cavity. OBJECTIVES: We reviewed the outcomes of CI and proposed surgical management principles according to the presentation status of CWD mastoidectomy cavity. MATERIAL AND METHODS: The cases of eight patients (nine ears) with CWD mastoidectomy cavity who underwent CI were retrospectively reviewed. The basis of the surgical decision, postoperative complications, and postimplant auditory performance were analysed. RESULTS: In seven patients (eight ears), implantation was performed in a single stage; in six ears, the external auditory canal (EAC) was oversewn. In two patients with ossification, the electrode array was inserted into the scala tympani by drilling of the basal turn or in the second turn of the cochlea through a drill-out procedure. Seven patients had a follow-up of 12-50 months and one patient was lost to follow-up. None of the followed-up seven patients suffered complications. CONCLUSIONS: CI is safe and effective in patients with profound hearing loss after radical mastoidectomy. In patients with CWD mastoidectomy cavity, CI does not cause a higher rate of postoperative complications relative to standard CI procedures. The outcome is excellent and comparable to that in the general CI population.

Prognostic Value of Neutrophil to Lymphocyte Ratio for In-hospital Mortality in Elderly Patients with Acute Myocardial Infarction / 华中科技大学学报（医学）（英德文版）

Coronary artery disease (CAD) is a multifactorial disease in which inflammation plays a central role.This study aimed to investigate the association of inflammatory markers such as the neutrophil to lymphocyte ratio (NLR),the Global Registry of Acute Coronary Events (GRACE) score with in-hospital mortality of elderly patients with acute myocardial infarction (AMI) in an attempt to explore the prognostic value of these indices for elderly AMI patients.One thousand consecutive CAD patients were divided into two groups based on age 60.The laboratory and clinical characteristics were assessed retrospectively by reviewing the medical records.The NLR and GRACE score were calculated.In the elderly (≥60 years),patients with non-ST-elevation myocardial infarction (NSTEMI) and ST-elevation myocardial infarction (STEMI) had significantly higher NLR than did those with unstable angina (UA) and stable angina pectoris (SAP) (P＜0.01).The NLR was considerably elevated in older AMI patients compared with their younger counterparts (＜60 years) (P＜0.05).In elderly AMI patients,the NLR was considerably higher in the high-risk group than in both the low-risk and medium-risk groups based on the GRACE score (P＜0.05 and P＜0.01,respectively),and the NLR was positively correlated with the GRACE score (r=0.322,P＜0.001).Either the NLR level or the GRACE score was significantly higher in the death group than in the surviving group (P＜0.05).By curve receiver operator characteristic curve (ROC) analysis,the optimal cut-off levels of 9.41 for NLR and 174 for GRACE score predicted in-hospital death [ROC area under the curve (AUC) 0.771 and 0.787,respectively,P＜0.001].It was concluded that an elevated NLR is a potential predictor of in-hospital mortality in elderly patients with AMI.

Prognostic Value of Neutrophil to Lymphocyte Ratio for In-hospital Mortality in Elderly Patients with Acute Myocardial Infarction / 华中科技大学学报（医学）（英德文版）

Coronary artery disease (CAD) is a multifactorial disease in which inflammation plays a central role.This study aimed to investigate the association of inflammatory markers such as the neutrophil to lymphocyte ratio (NLR),the Global Registry of Acute Coronary Events (GRACE) score with in-hospital mortality of elderly patients with acute myocardial infarction (AMI) in an attempt to explore the prognostic value of these indices for elderly AMI patients.One thousand consecutive CAD patients were divided into two groups based on age 60.The laboratory and clinical characteristics were assessed retrospectively by reviewing the medical records.The NLR and GRACE score were calculated.In the elderly (≥60 years),patients with non-ST-elevation myocardial infarction (NSTEMI) and ST-elevation myocardial infarction (STEMI) had significantly higher NLR than did those with unstable angina (UA) and stable angina pectoris (SAP) (P＜0.01).The NLR was considerably elevated in older AMI patients compared with their younger counterparts (＜60 years) (P＜0.05).In elderly AMI patients,the NLR was considerably higher in the high-risk group than in both the low-risk and medium-risk groups based on the GRACE score (P＜0.05 and P＜0.01,respectively),and the NLR was positively correlated with the GRACE score (r=0.322,P＜0.001).Either the NLR level or the GRACE score was significantly higher in the death group than in the surviving group (P＜0.05).By curve receiver operator characteristic curve (ROC) analysis,the optimal cut-off levels of 9.41 for NLR and 174 for GRACE score predicted in-hospital death [ROC area under the curve (AUC) 0.771 and 0.787,respectively,P＜0.001].It was concluded that an elevated NLR is a potential predictor of in-hospital mortality in elderly patients with AMI.

Predictive value of neutrophil to lymphocyte ratio for inhospital mortality in type 2 diabetic patients with acute myocardial infarction / 中华内分泌代谢杂志

Objective To explore the prognostic value of biomarkers in type 2 diabetic patients with acute myocardial infarction (AMI), this study was to investigate the associations between the neutrophil to lymphocyte ratio (NLR), the Global Registry of Acute Coronary Events (GRACE) score and in-hospital mortality. MethodsSeven hundred and seven consecutive AMI patients were divided into diabetic group (DM-AMI group), impaired glucose tolerance group (IGT-AMI group), and normal glycemic group (NGT-AMI group). The laboratory and clinical characteristics were assessed retrospectively from the medical records. The NLR and GRACE score were calculated. Results In AMI patients, the DM-AMI group had significantly higher NLR and GRACE scores compared with those from the IGT-AMI group and NGT-AMI group (P>=Neutrophil to lymphocyte ratio; In-hospital mortality; Acute myocardial infarction; Diabetes mellitus, type 2

Research advance of posterior ischemic optic neuropathy / 国际眼科杂志(Guoji Yanke Zazhi)

Posterior ischemic optic neuropathy is a kind of ischemic optic neuropathy, the incidence rate of which is lower with less obviously clinical features, less positive signs and more difficultly diagnosis when compared with anterior ischemic optic neuropathy.Meanwhile, therapeutic method of posterior ischemic optic neuropathy has remained controversial.This article will summarize the research development of the auxiliary examination, diagnosis, differential diagnosis and therapeutic method of posterior ischemic optic neuropathy.