Metagenomic next-generation sequencing reveals co-infection with Legionella pneumophila and Fusobacterium necrophorum in a patient with severe pneumonia: a case report.

BACKGROUND: Legionella pneumonia is one of the most severe types of atypical pneumonia, impairing multiple organ systems, posing a threat to life. Diagnosing Legionella pneumonia is challenging due to difficulties in culturing the bacteria and limitations in immunoassay sensitivity and specificity. CASE PRESENTATION: This paper reports a rare case of sepsis caused by combined infection with Legionella pneumophila and Fusobacterium necrophorum, leading to respiratory failure, acute kidney injury, acute liver injury, myocardial damage, and electrolyte disorders. In addition, we systematically reviewed literature on patients with combined Legionella infections, analyzing their clinical features, laboratory results and diagnosis. CONCLUSIONS: For pathogens that require prolonged incubation periods and are less sensitive to conventional culturing methods, metagenomic next-generation sequencing (mNGS) can be a powerful supplement to pathogen screening and plays a significant role in the auxiliary diagnosis of complex infectious diseases.

m6A RNA methylation-mediated NDUFA4 promotes cell proliferation and metabolism in gastric cancer.

Gastric cancer (GC) is a malignancy with poor prognosis. NDUFA4 is reported to correlate with the progression of GC. However, its underlying mechanism in GC is unknown. Our study was to reveal the pathogenic mechanism of NDUFA4 in GC. NDUFA4 expression was explored in single-cell and bulk RNA-seq data as well as GC tissue microarray. Mitochondrial respiration and glycolysis were estimated by oxygen consumption rate and extracellular acidification rate, respectively. The interaction between NDUFA4 and METTL3 was validated by RNA immunoprecipitation. Flow cytometry was used to estimate cell cycle, apoptosis and mitochondrial activities. NDUFA4 was highly expressed in GC and its high expression indicated a poor prognosis. The knockdown of NDUFA4 could reduce cell proliferation and inhibit tumor growth. Meanwhile, NDUFA4 could promote glycolytic and oxidative metabolism in GC cells, whereas the inhibition of glycolysis suppressed the proliferation and tumor growth of GC. Besides, NDUFA4 inhibited ROS level and promoted MMP level in GC cells, whereas the inhibition of mitochondrial fission could reverse NDUFA4-induced glycolytic and oxidative metabolism and tumor growth of GC. Additionally, METTL3 could increase the m6A level of NDUFA4 mRNA via the m6A reader IGF2BP1 to promote NDUFA4 expression in GC cells. Our study revealed that NDUFA4 was increased by m6A methylation and could promote GC development via enhancing cell glycolysis and mitochondrial fission. NDUFA4 was a potential target for GC treatment.

Arsenic exposures and prostate cancer risk: A multilevel meta-analysis.

OBJECTIVE: Previous studies found that arsenic exposures have been linked to prostate cancer risk. However, this finding has been inconsistent. The purpose of this paper was to estimate the effects of arsenic exposures on prostate cancer risk. METHOD: We conducted a meta-analysis of epidemiologic studies of arsenic exposures and prostate cancer risk. We searched for both arsenic exposure and prostate cancer studies published until January 2021 from the following electronic databases: PubMed, Scopus, and Web of Science. Multilevel meta-analysis via random-effects modeling was used to examine the association between arsenic exposures and prostate cancer risk. RESULTS: There were 12 studies included with an effect size of 23. Arsenic exposure was determined from water and soil (n = 8), urinary measurements (n = 2), or self-reported questionnaire (n = 2). Overall, arsenic exposure was found to be statistically significantly associated with prostate cancer risk (Relative risk [RR] = 1.18, 95% confidence interval [CI]: 1.06 - 1.30). In the sub-analysis, arsenic exposure from water and soil was found to be statistically significantly associated with prostate cancer risk (RR= 1.22, 95% CI: 1.05 - 1.41). CONCLUSION: Data suggest that arsenic exposures may play a role in increasing prostate cancer risk. Further prospective studies are warranted to verify the association between arsenic exposure and prostate cancer risk.

Polyaminoglycoside-mediated cell reprogramming system for the treatment of diabetes mellitus.

Diabetes mellitus is a disease of metabolism, featuring persistent hyperglycaemia due to insufficient insulin secretion or insulin resistance. At present, the generation of new beta cells from autologous cells by ectopic expression of specific transcription factors is a promising treatment for diabetes. The application of this strategy urgently needs safe and effective gene delivery vectors. In this work, a therapeutic plasmid (pNPMN-PBase), combined multiple specific transcription factors Ngn3, Pdx1, Mafa and Neruod1 (NPMN), was firstly constructed. Then, phenylboronic acid (PBA)-functionalized branched polymers (SS-HPT-P) have been proposed to deliver pNPMN-PBasefor the promising treatment of diabetes. SS-HPT-P had good biocompatibility and low cytotoxicity, and could achieve liver-targeted delivery. SS-HPT-P/pNPMN-PBase system can effectively realize the liver delivery of exogenous therapeutic genes, induce the reprogramming of hepatocytes into beta-like cells, reestablish the endogenous insulin-expression system, and alleviate diabetes and its complications. The present study thus provides an effective strategy for the cell replacement therapy of diabetes.

Virtual Screening for Novel SarA Inhibitors to Prevent Biofilm Formation of Staphylococcus aureus in Prosthetic Joint Infections.

Staphylococcus aureus is one of the predominant causes of periprosthetic joint infections (PJIs). Bacterial adhesion and biofilm formation are important factors in the pathogenesis of PJIs. S. aureus biofilm formation is regulated by several factors, including S. aureus regulator A (SarA). Previous studies have found that SarA mutants have limited ability to develop biofilms. In this study, we identified a SarA-targeting antibiofilm compound, ZINC00990144, and evaluated its efficacy and toxicity. According to static biofilm assay, the antibiofilm ability of the compound was concentration dependent. ZINC00990144 reduced biofilm in multiple strains by 40-86% at a concentration of 11.5 µM. Additionally, ZINC00990144 inhibited biofilm formation on different orthopedic implant materials including Titanium and UHMWPE disc. Furthermore, quantitative polymerase chain reaction results demonstrated that ZINC00990144 upregulated the expression of S. aureus exoproteases to inhibit the formation of biofilms. Moreover, ZINC00990144 prevented biofilm formation when exposed to sub-inhibitory doses of vancomycin, which is known to promote biofilm formation. CCK-8 results demonstrated ZINC00990144 has no significant effect on cell viability at concentration of 11.5 µM or below. Finally, we verified the antibiofilm function of the compound in vivo using implant infection mice model with/without exposure to sub-inhibitory vancomycin. In conclusion, ZINC00990144 acts by modulating between biofilm and planktonic state of S. aureus instead of being bactericidal. Therefore, it has the potential to be used in combination with other antibiotics to prevent PJIs.

Risk of suicidal ideation, suicide attempts, and suicide deaths in persons with sleep apnea: Protocol for a systematic review and meta-analysis.

AIM: To estimate the pooled prevalence and incidence of suicidal ideation, attempts, and deaths in people with sleep apnea. METHOD: We will identify epidemiological studies reporting the prevalence or incidence rate of suicide in people with sleep apnea. We will search the following databases: PubMed (MEDLINE), Scopus, Cochrane Library, OVID (HEALTH STAR), OVID (MEDLINE) and Joana Briggs Institute EBF Database. No age, geographical location, study-design or language limits will be applied. This protocol was developed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) guidelines. Two reviewers (YY and YP) will independently screen citations, abstracts and will identify full-text articles for inclusion, extract data, and appraise the quality and bias of included studies. Discrepancies will be resolved by consulting with a third researcher (MC). Study quality will be assessed by the Newcastle-Ottawa Scale. The primary outcomes will be the overall prevalence or incidence of suicidal ideation, attempts and completion and the risk of suicide in people with sleep apnea. For pooling of the studies, we will use a random-effects model with a logit transformation. The DerSimonian and Laird (DL) random-effects method will be used to estimate the pooled inter-study variance. We will assess the between-study heterogeneity using I2 statistics, and Cochrane's Q statistic (significance level < 0.05). If the I2 is high (>75%), we will perform subgroup meta-analyses and conduct a meta-regression analysis to explore sources of study heterogeneity using study level median age, study-level proportions of race, gender, depression and quality scores. We will report effect estimates as suicide risk per 1000 individuals. Egger's test and funnel plots will be used to assess publication bias, and adjusted estimates using trim and fill methods will be reported if publication bias is suspected. ETHICS AND DISSEMINATION: No ethics clearance is required as no primary data will be collected. The results of this systematic review and meta-analysis will be presented at scientific conferences and published in a peer-review journal. The results may shed more light on the burden of suicide risk among individuals with sleep apnea and may guide future population-specific interventions. TRIAL REGISTRATION: PROSPERO registration number: CRD42020165404.

Hyaluronic acid-modified hydrothermally synthesized iron oxide nanoparticles for targeted tumor MR imaging.

We report a polyethyleneimine (PEI)-mediated approach to synthesizing hyaluronic acid (HA)-targeted magnetic iron oxide nanoparticles (Fe3O4 NPs) for in vivo targeted tumor magnetic resonance (MR) imaging applications. In this work, Fe3O4 NPs stabilized by PEI were first synthesized via a one-pot hydrothermal method. The formed PEI-stabilized Fe3O4 NPs were then modified with fluorescein isothiocyanate (FI) and HA with two different molecular weights to obtain two different Fe3O4 NPs (Fe3O4-PEI-FI-HA6K and Fe3O4-PEI-FI-HA31K NPs) with a size of 15-16 nm. The formed HA-modified multifunctional Fe3O4 NPs were characterized via different techniques. We show that the multifunctional Fe3O4 NPs are water-dispersible and colloidal stable in different aqueous media. In vitro cell viability and hemolysis studies reveal that the particles are quite cytocompatible and hemocompatible in the given concentration range. Furthermore, confocal microscopy and flow cytometry data demonstrate that HA-targeted Fe3O4 NPs are able to be uptaken specifically by cancer cells overexpressing CD44 receptors, and be used as efficient probes for targeted MR imaging of cancer cells in vitro and xenografted tumor models in vivo. With the tunable amine-based conjugation chemistry, the PEI-stabilized Fe3O4 NPs may be functionalized with other biological ligands or drugs for diagnosis and therapy of different biological systems.