mediated cancer therapy has achieved remarkable anti-tumor effects in experimental animal models, but the detailed mechanism remains unsolved. In this report, the active involvement of the host immune response in this process was confirmed by comparing the tumor-suppressive effects of Salmonella in immunocompetent and immunodeficient mice bearing melanoma allografts. Since flagella are key inducers of the host immune response during bacterial infection, flagella were genetically disrupted to analyse their involvement in Salmonella-mediated cancer therapy. The results showed that flagellum-deficient strains failed to induce significant anti-tumor effects, even when more bacteria were administered to offset the difference in invasion efficiency. Flagella mainly activate immune cells via Flagellin/Toll-like receptor 5 (TLR5) signalling pathway. Indeed, we showed that exogenous activation of TLR5 signalling by recombinant Flagellin and exogenous expression of TLR5 both enhanced the therapeutic efficacy of flagellum-deficient Salmonella against melanoma. Our study highlighted the therapeutic value of the interaction between Salmonella and the host immune response through Flagellin/TLR5 signalling pathway during Salmonella-mediated cancer therapy, thereby suggesting the potential application of TLR5 agonists in the cancer immune therapy.

Parkinson\'s disease (PD) is the second most common neurodegenerative disease, but none of the current treatments for PD can halt the progress of the disease due to the limited understanding of the pathogenesis. In PD development, the communication between the brain and the gastrointestinal system influenced by gut microbiota is known as microbiota-gut-brain axis. However, the explicit mechanisms of microbiota dysbiosis in PD development have not been well elucidated yet. FLZ, a novel squamosamide derivative, has been proved to be effective in many PD models and is undergoing the phase I clinical trial to treat PD in China. Moreover, our previous pharmacokinetic study revealed that gut microbiota could regulate the absorption of FLZ in vivo. The aims of our study were to assess the protective effects of FLZ treatment on PD and to further explore the underlying microbiota-related mechanisms of PD by using FLZ as a tool. In the current study, chronic oral administration of rotenone was utilized to induce a mouse model to mimic the pathological process of PD. Here we revealed that FLZ treatment alleviated gastrointestinal dysfunctions, motor symptoms, and dopaminergic neuron death in rotenone-challenged mice. 16S rRNA sequencing found that PD-related microbiota alterations induced by rotenone were reversed by FLZ treatment. Remarkably, FLZ administration attenuated intestinal inflammation and gut barrier destruction, which subsequently inhibited systemic inflammation. Eventually, FLZ treatment restored blood-brain barrier structure and suppressed neuroinflammation by inhibiting the activation of astrocytes and microglia in the substantia nigra (SN). Further mechanistic research demonstrated that FLZ treatment suppressed the TLR4/MyD88/NF-κB pathway both in the SN and colon. Collectively, FLZ treatment ameliorates microbiota dysbiosis to protect the PD model via inhibiting TLR4 pathway, which contributes to one of the underlying mechanisms beneath its neuroprotective effects. Our research also supports the importance of microbiota-gut-brain axis in PD pathogenesis, suggesting its potential role as a novel therapeutic target for PD treatment.

BACKGROUND: Multiple infection outbreaks have been linked to contaminated duodenoscopes worldwide. However, the contamination rate of patient-ready duodenoscopes varies highly amongst published studies testing this subject. We aimed to estimate the contamination rate of reprocessed patient-ready duodenoscopes for endoscopic retrograde cholangio-pancreatography (ERCP) based on currently available data.
METHODS: We searched the PubMed and Embase databases from January 1, 2010 until March 10, 2020, for citations investigating contamination rates of reprocessed patient-ready duodenoscopes. Studies not assessing other types of endoscopes than duodenoscopes were excluded from the analysis. Study eligibility and data extraction was evaluated by three reviewers independently. A random-effects model (REM) based on the proportion distribution was used to calculate the pooled total contamination rate of reprocessed patient-ready duodenoscopes. Subgroup analyses were carried out to assess contamination rates when using different reprocessing methods by comparing single high-level disinfection (HLD) with double HLD and ethylene oxide (EtO) gas sterilization. Additionally, we investigated the contamination rate between studies conducted following an outbreak compared to non-outbreak-initiated studies.
RESULTS: We identified 15 studies that fulfilled the inclusion, which included 925 contaminated duodenoscopes from 13,112 samples. The calculated total weighted contamination rate was 15.25% ± 0.018 (95% confidence interval [Cl]: 11.74% - 18.75%). The contamination rate after only using HLD was 16.14% ± 0.019 (95% Cl: 12.43% - 19.85%) and after using either dHLD or EtO the contamination rate decreased to 9.20% ± 0.025 (95% Cl: 4.30% - 14.10%). Studies conducted following an outbreak (n=4) showed a 5.72% ± 0.034 (95% Cl: 0.00% - 12.43%) contamination rate, and non-outbreak-initiated studies (n=11) revealed a contamination rate of 21.50% ± 0.031 (95% Cl: 15.35% - 27.64%).
CONCLUSIONS: This is the first meta-analysis to estimate the contamination rate of patient-ready duodenoscopes used for ERCP. Based on the available literature, our analysis demonstrates that there is a 15.25% contamination rate of reprocessed patient-ready duodenoscopes. Additionally, the analysis indicates that dHLD and EtO reprocessing methods are superior to single HLD but still not efficient in regards to cleaning the duodenoscopes properly. Furthermore, studies conducted following an outbreak did not entail a higher contamination rate compared to non-outbreak-initiated studies.
BACKGROUND: The authors received no financial support for the research, authorship, and/or publication of this article.

Coinoculation of plants with mixtures of beneficial microbes sometimes produces synergistic effects. In this study, the effect of soybean coinoculation with the N2-fixing Bradyrhizobium japonicum E109 and the biocontrol fungus Trichoderma harzianum Th5cc was analyzed. Nodulation by E109 was not hampered by Th5cc, which antagonized five out of seven soybean pathogens tested. Furthermore, Th5cc relieved nitrate-inhibition of nodulation, enabling the formation of nodules containing infected cells with bacteroids in the presence of the otherwise inhibitory 10 mM KNO3. Th5cc released micromolar amounts of auxin, and addition of 11 μM indoleacetic acid to soybean plants inoculated with E109 in the absence of Th5cc also induced nodulation in the presence of 10 mM KNO3. Thus, Th5cc may release auxins into the soybean rhizosphere, which hormones might participate in overcoming the nitrate-inhibition of nodulation. Our results suggest that soybean plants coinoculated with these microorganisms might benefit from biocontrol while contributing to soil-nitrogen preservation.

ProBiotic-4 is a probiotic preparation composed of Bifidobacterium lactis, Lactobacillus casei, Bifidobacterium bifidum, and Lactobacillus acidophilus. This study aims to investigate the effects of ProBiotic-4 on the microbiota-gut-brain axis and cognitive deficits, and to explore the underlying molecular mechanism using senescence-accelerated mouse prone 8 (SAMP8) mice. ProBiotic-4 was orally administered to 9-month-old SAMP8 mice for 12 weeks. We observed that ProBiotic-4 significantly improved the memory deficits, cerebral neuronal and synaptic injuries, glial activation, and microbiota composition in the feces and brains of aged SAMP8 mice. ProBiotic-4 substantially attenuated aging-related disruption of the intestinal barrier and blood-brain barrier, decreased interleukin-6 and tumor necrosis factor-α at both mRNA and protein levels, reduced plasma and cerebral lipopolysaccharide (LPS) concentration, toll-like receptor 4 (TLR4) expression, and nuclear factor-κB (NF-κB) nuclear translocation in the brain. In addition, not only did ProBiotic-4 significantly decreased the levels of γ-H2AX, 8-hydroxydesoxyguanosine, and retinoic-acid-inducible gene-I (RIG-I), it also abrogated RIG-I multimerization in the brain. These findings suggest that targeting gut microbiota with probiotics may have a therapeutic potential for the deficits of the microbiota-gut-brain axis and cognitive function in aging, and that its mechanism is associated with inhibition of both TLR4-and RIG-I-mediated NF-κB signaling pathway and inflammatory responses.

Any manipulation on open bowel causes interventional impact on gut microbiome, and surgical stress triggers bacterial translocation; thus, it will be fundamental to determine gut microbiome after surgery. Monitoring dynamic changes in microbiome of post-surgical infants who received probiotics and placebo could provide with important information about gut colonization and potential bacterial overgrowth. The purpose of this study is to assess the effect of probiotics supplementation on length of hospital stay, duration of parenteral nutrition, and feed tolerance in neonates after gastrointestinal surgery.

Analogues of the anti-tuberculosis drug bedaquiline, bearing a 3,5-dimethoxy-4-pyridyl C-unit, retain high anti-bacterial potency yet exert less inhibition of the hERG potassium channel, in vitro, than the parent compound. Two of these analogues (TBAJ-587 and TBAJ-876) are now in preclinical development. The present study further explores structure-activity relationships across a range of related 3,5-disubstituted-4-pyridyl C-unit bedaquiline analogues of greatly varying lipophilicity (clogP from 8.16 to 1.89). This broader class shows similar properties to the 3,5-dimethoxy-4-pyridyl series, being substantially more potent in vitro and equally active in an in vivo (mouse) model than bedaquiline, while retaining a lower cardiovascular risk profile through greatly attenuated hERG inhibition.

The severity of pneumonia in respiratory syncytial virus (RSV) infection is strongly related to host immune response and external factors such as bacteria and environmental chemicals. We investigated the effect of inactivated Streptococcus pneumoniae (ISP) as non-pathogenic particles on the severity of pneumonia in RSV-infected mice. Mice were intranasally exposed to ISP before RSV infection. On day 5 post-infection, we examined tissues, virus titer, and infiltrated cells in the lungs. The ISP did not cause significant histopathological effects in the lungs of RSV infected mice, but reduced virus titer. It also reduced the ratio of lymphocyte infiltration into the lungs and consequently the ratio of macrophage increased. In addition, we found that ISP increased RANTES level in bronchoalveolar lavage fluid from RSV-infected mice on day 1 post-infection, but reduced type I interferon levels. Thus, ISP did not exacerbate pneumonia in RSV infection, rather, it might mildly reduce the severity. We characterize and discuss the inherent activity of ISP as non-pathogenic particles inducing the role of RANTES on the pneumonia in RSV infection.

Bedaquiline is a new drug of the diarylquinoline class that has proven to be clinically effective against drug-resistant tuberculosis, but has a cardiac liability (prolongation of the QT interval) due to its potent inhibition of the cardiac potassium channel protein hERG. Bedaquiline is highly lipophilic and has an extremely long terminal half-life, so has the potential for more-than-desired accumulation in tissues during the relatively long treatment durations required to cure TB. The present work is part of a program that seeks to identify a diarylquinoline that is as potent as bedaquiline against Mycobacterium tuberculosis, with lower lipophilicity, higher clearance, and lower risk for QT prolongation. Previous work led to the identification of compounds with greatly-reduced lipophilicity compounds that retain good anti-tubercular activity in vitro and in mouse models of TB, but has not addressed the hERG blockade. We now present compounds where the C-unit naphthalene is replaced by a 3,5-dialkoxy-4-pyridyl, demonstrate more potent in vitro and in vivo anti-tubercular activity, with greatly attenuated hERG blockade. Two examples of this series are in preclinical development.

The seamless ligation cloning extract (SLiCE) method is a novel seamless DNA cloning tool that utilizes homologous recombination activities in Escherichia coli cell lysates to assemble DNA fragments into a vector. Several laboratory E. coli strains can be used as a source for the SLiCE extract; therefore, the SLiCE-method is highly cost-effective.The SLiCE has sufficient cloning ability to support conventional DNA cloning, and can simultaneously incorporate two unpurified DNA fragments into vector. Recently, many seamless DNA cloning kits have become commercially available; these are generally very convenient, but expensive. In this study, we evaluated the cloning efficiencies between a simple and highly cost-effective SLiCE-method and a commercial kit under various molar ratios of insert DNA fragments to vector DNA. This assessment identified that the SLiCE from a laboratory E. coli strain yielded 30-85% of the colony formation rate of a commercially available seamless DNA cloning kit. The cloning efficiencies of both methods were highly effective, exhibiting over 80% success rate under all conditions examined. These results suggest that SLiCE from a laboratory E. coli strain can efficiently function as an effective alternative to commercially available seamless DNA cloning kits.