Genesis of a novel Shigella flexneri serotype by sequential infection of serotype-converting bacteriophages SfX and SfI

<p>Abstract</p> <p>Background</p> <p><it>Shigella flexneri </it>is the major pathogen causing bacillary dysentery. Fifteen serotypes have been recognized up to now. The genesis of new <it>S. flexneri </it>serotypes is commonly mediated by serotype-converting bacteriophages. Untypeable or novel serotypes from natural infections had been reported worldwide but have not been generated in laboratory.</p> <p>Results</p> <p>A new <it>S. flexneri </it>serotype-serotype 1 d was generated when a <it>S. flexneri </it>serotype Y strain (native LPS) was sequentially infected with 2 serotype-converting bacteriophages, SfX first and then SfI. The new serotype 1 d strain agglutinated with both serotype X-specific anti-7;8 grouping serum and serotype 1a-specific anti- I typing serum, and differed from subserotypes 1a, 1b and 1c. Twenty four <it>S. flexneri </it>clinical isolates of serotype X were all converted to serotype 1 d by infection with phage SfI. PCR and sequencing revealed that SfI and SfX were integrated in tandem into the <it>proA-yaiC </it>region of the host chromosome.</p> <p>Conclusions</p> <p>These findings suggest a new <it>S. flexneri </it>serotype could be created in nature. Such a conversion may be constrained by susceptibility of a strain to infection by a given serotype-converting bacteriophage. This finding has significant implications in the emergence of new <it>S. flexneri </it>serotypes in nature.</p

The impact of immunoglobulin G N-glycosylation level on COVID-19 outcome: evidence from a Mendelian randomization study

BackgroundThe coronavirus disease 2019 (COVID-19) pandemic has exerted a profound influence on humans. Increasing evidence shows that immune response is crucial in influencing the risk of infection and disease severity. Observational studies suggest an association between COVID‐19 and immunoglobulin G (IgG) N-glycosylation traits, but the causal relevance of these traits in COVID-19 susceptibility and severity remains controversial.MethodsWe conducted a two-sample Mendelian randomization (MR) analysis to explore the causal association between 77 IgG N-glycosylation traits and COVID-19 susceptibility, hospitalization, and severity using summary-level data from genome-wide association studies (GWAS) and applying multiple methods including inverse-variance weighting (IVW), MR Egger, and weighted median. We also used Cochran’s Q statistic and leave-one-out analysis to detect heterogeneity across each single nucleotide polymorphism (SNP). Additionally, we used the MR-Egger intercept test, MR-PRESSO global test, and PhenoScanner tool to detect and remove SNPs with horizontal pleiotropy and to ensure the reliability of our results.ResultsWe found significant causal associations between genetically predicted IgG N-glycosylation traits and COVID-19 susceptibility, hospitalization, and severity. Specifically, we observed reduced risk of COVID-19 with the genetically predicted increased IgG N-glycan trait IGP45 (OR = 0.95, 95% CI = 0.92–0.98; FDR = 0.019). IGP22 and IGP30 were associated with a higher risk of COVID-19 hospitalization and severity. Two (IGP2 and IGP77) and five (IGP10, IGP14, IGP34, IGP36, and IGP50) IgG N-glycosylation traits were causally associated with a decreased risk of COVID-19 hospitalization and severity, respectively. Sensitivity analyses did not identify any horizontal pleiotropy.ConclusionsOur study provides evidence that genetically elevated IgG N-glycosylation traits may have a causal effect on diverse COVID-19 outcomes. Our findings have potential implications for developing targeted interventions to improve COVID-19 outcomes by modulating IgG N-glycosylation levels

Effects of Thiazolidinedione Therapy on Inflammatory Markers of Type 2 Diabetes: A Meta-Analysis of Randomized Controlled Trials

<div><p>Background</p><p>Inflammation is a common feature in patients with type 2 diabetes mellitus (T₂DM). This meta-analysis aimed to assess the influence of thiazolidinedione (TZD) therapy on the circulating levels of inflammatory markers in patients with T₂DM.</p><p>Methods and Results</p><p>We searched the databases Medline, Embase, ScienceDirect, Web of Science, SpringerLink, and the Cochrane Library for randomized controlled trials (RCTs) that examined the effects of thiazolidinedione vs. a placebo on patients with T₂DM. The main outcomes were absolute changes in levels of circulating inflammatory markers. Twenty-seven RCTs were included and data were analyzed using a fixed-effect model or a random-effect model based on heterogeneity. Pooled results indicated that circulating levels of high-sensitivity C reactive protein (hsCRP; SMD = –0.65, 95% CI = –0.98 to –0.32, <i>p</i> < 0.01), monocyte chemoattractant protein-1 (MCP-1; WMD = –54.19, 95% CI = –73.86 to –34.52, <i>p</i> < 0.01), von Willebrand factor% (vWF%; WMD = –8.18, 95% CI = –13.54 to –2.81, <i>p</i> 0.01), fibrinogen (SMD = –0.26, 95% CI = –0.41 to –0.11, <i>p</i> < 0.01) and E-selectin(WMD = –3.57, 95% CI = –5.59 to -1.54, <i>p</i> <0.01) were significantly decreased after TZD therapy. However, interleukin-6 (IL-6), matrix metalloproteinase-9 (MMP-9), soluble CD40 ligand, plasminogen activator inhibitor 1 (PAI-1) and intercellular adhesion molecule (ICAM-1) were not significantly affected. Subgroup analyses of PAI-1, vWF% and fibrinogen in terms of trial drugs showed significant reductions for rosiglitazone (all <i>p</i> valuses< 0.05), but not pioglitazone treatment. Conversely, the E-selectin (<i>p</i> < 0.01) lowering effect only existed in the pioglitazone group. Further, rosiglitazone and pioglitazone treatment reduced serum hsCRP and MCP-1 but had no marked effects on MMP-9, IL-6 and ICAM-1.</p><p>Conclusions</p><p>Limited evidence suggested that TZD therapy had anti-inflammatory property that might contribute to its beneficial effect on inflammatory state in patients with type 2 diabetes.</p></div

DUB3 is a MAGEA3 deubiquitinase and a potential therapeutic target in hepatocellular carcinoma

Summary: Although melanoma-associated antigen A3 and A6 (MAGEA3/6)-specific tumor vaccines have shown antitumor effects in melanoma and non-small cell lung cancer (NSCLC), many cancers do not respond because MAGEA3 can promote cancer without triggering an immune response. Here, we identified DUB3 as the MAGEA3 deubiquitinase. DUB3 interacts with, deubiquitinates and stabilizes MAGEA3. Depletion of DUB3 in hepatocellular carcinoma (HCC) cells results in MAGEA3 degradation and P53-dependent growth inhibition. Moreover, DUB3 knockout attenuates HCC tumorigenesis in vivo, which can be rescued by restoration of MAGEA3. Intriguingly, pharmacological inhibition of DUB3 by palbociclib promotes degradation of MAGEA3 and inhibits tumor growth in preclinical models implanted with parental HCC cells but not with DUB3 knockout HCC cells. In patients with HCC, DUB3 is highly expressed, and its levels positively correlate with MAGEA3 levels. Taken together, DUB3 is a MAGEA3 deubiquitinase, and abrogating DUB3 enzymatic activity by palbociclib is a promising therapeutic strategy for HCC

Synchronous Cr(VI) Remediation and Energy Production Using Microbial Fuel Cell from a Subsurface Environment: A Review

Applying microbial fuel cell (MFC) technology for eco-remediation of Cr(VI) pollution from a subsurface environment has great scientific value and practical significance due to its promising advantages of pollutant remediation and renewable energy generation. The aim of the current review is to summarize the migration characteristics of Cr(VI) in a subsurface soil/water environment and investigate the factors affecting the MFC performance for synchronous Cr(VI) remediation and power generation, and sequentially highlight diverse challenges of MFC technology for in situ remediation of subsurface groundwater and soils. The critical review put forward that Cr(VI) removal efficiency and energy production of MFC can be improved by enhancing the adjustability of cathode pH, setting potential, modifying electrode, and incorporating other technologies into MFC. It was recommended that designing typical large-scale, long-term continuous flow MFC systems, adding electron shuttle media or constructing artificial electron according to actual groundwater/soil and Cr(VI) pollution characteristics, site geology, and the hydrogeology condition (hydrochemical conditions, colloid type, and medium) are essential to overcome the limitations of the small size of the laboratory experiments and improve the application of technology to in situ Cr(VI) remediation. This review provided reference and ideas for future research of MFC-mediated onsite Cr(VI) remediation

Overview and characteristics of included studies.

<p>TZDs = thiazolidinediones, P = pioglitazone, R = rosiglitazone, Ra = random, DB = double bind, SB = single blind, PC = placebo-controlled, T₂DM = type 2 diabetes,CAD = coronary artery disease.</p><p>Overview and characteristics of included studies.</p

Process of study selection.

<p>Process of study selection.</p

Forest plots from meta-analysis of RCTs regarding the role of thiazolidinedinediones therapy in plasma concentrations of pro-inflammatory markers hsCRP(A), IL-6(B), MMP-9(C), sCD40L(D) and MCP-1(E).

<p>Forest plots from meta-analysis of RCTs regarding the role of thiazolidinedinediones therapy in plasma concentrations of pro-inflammatory markers hsCRP(A), IL-6(B), MMP-9(C), sCD40L(D) and MCP-1(E).</p