BACKGROUND:The impact of gut microbiota on the regulation of host physiology has recently garnered considerable attention, particularly in key areas such as the immune system and metabolism. These ...areas are also crucial for the pathophysiology of and repair after myocardial infarction (MI). However, the role of the gut microbiota in the context of MI remains to be fully elucidated.
METHODS:To investigate the effects of gut microbiota on cardiac repair after MI, C57BL/6J mice were treated with antibiotics 7 days before MI to deplete mouse gut microbiota. Flow cytometry was applied to examine the changes in immune cell composition in the heart. 16S rDNA sequencing was conducted as a readout for changes in gut microbial composition. Short-chain fatty acid (SCFA) species altered after antibiotic treatment were identified by high-performance liquid chromatography. Fecal reconstitution, transplantation of monocytes, or dietary SCFA or Lactobacillus probiotic supplementation was conducted to evaluate the cardioprotective effects of microbiota on the mice after MI.
RESULTS:Antibiotic-treated mice displayed drastic, dose-dependent mortality after MI. We observed an association between the gut microbiota depletion and significant reductions in the proportion of myeloid cells and SCFAs, more specifically acetate, butyrate, and propionate. Infiltration of CX3CR1+ monocytes to the peri-infarct zone after MI was also reduced, suggesting impairment of repair after MI. Accordingly, the physiological status and survival of mice were significantly improved after fecal reconstitution, transplantation of monocytes, or dietary SCFA supplementation. MI was associated with a reorganization of the gut microbial community such as a reduction in Lactobacillus. Supplementing antibiotic-treated mice with a Lactobacillus probiotic before MI restored myeloid cell proportions, yielded cardioprotective effects, and shifted the balance of SCFAs toward propionate.
CONCLUSIONS:Gut microbiota–derived SCFAs play an important role in maintaining host immune composition and repair capacity after MI. This suggests that manipulation of these elements may provide opportunities to modulate pathological outcome after MI and indeed human health and disease as a whole.
Palmitoyltransferase (PAT) catalyses protein S-palmitoylation which adds 16-carbon palmitate to specific cysteines and contributes to various biological functions. We previously reported that in ...mice, deficiency of Zdhhc13, a member of the PAT family, causes severe phenotypes including amyloidosis, alopecia, and osteoporosis. Here, we show that Zdhhc13 deficiency results in abnormal liver function, lipid abnormalities, and hypermetabolism. To elucidate the molecular mechanisms underlying these disease phenotypes, we applied a site-specific quantitative approach integrating an alkylating resin-assisted capture and mass spectrometry-based label-free strategy for studying the liver S-palmitoylome. We identified 2,190 S-palmitoylated peptides corresponding to 883 S-palmitoylated proteins. After normalization using the membrane proteome with TMT10-plex labelling, 400 (31%) of S-palmitoylation sites on 254 proteins were down-regulated in Zdhhc13-deficient mice, representing potential ZDHHC13 substrates. Among these, lipid metabolism and mitochondrial dysfunction proteins were overrepresented. MCAT and CTNND1 were confirmed to be specific ZDHHC13 substrates. Furthermore, we found impaired mitochondrial function in hepatocytes of Zdhhc13-deficient mice and Zdhhc13-knockdown Hep1-6 cells. These results indicate that ZDHHC13 is an important regulator of mitochondrial activity. Collectively, our study allows for a systematic view of S-palmitoylation for identification of ZDHHC13 substrates and demonstrates the role of ZDHHC13 in mitochondrial function and metabolism in liver.
Lactobacillus kefiranofaciens M1 is a novel probiotic strain that was isolated from kefir grains. Previously, we have demonstrated the immunoregulatory, anti-allergic, anti-asthmatic and anti-colitis ...abilities of L. kefiranofaciens M1 in a number of in-vitro and in-vivo experiments. However, whether the effects of L. kefiranofaciens M1 are elicited directly on the host or act by regulating the host's microbiota remains unknown. A number of studies have used germ-free or gnotobiotic animals to investigate the relationship between probiotics and colitis; therefore the aim of this study was to investigate the effects of L. kefiranofaciens M1 on germ-free mice. Such an approach should help in determining the direct effects of L. kefiranofaciens M1 on the host itself. Four-week-old female germ-free mice were inoculated intragastrically with 2×10(8) CFU/mouse L. kefiranofaciens M1 once or at 2-day intervals for 14 days. Bacterial colonization, the Th1/Th2 cytokine profile of the mice's splenocytes and the anti-colitis effect of L. kefiranofaciens M1 were investigated. The strongest response in terms of splenic Th1 cytokine IFN-γ and IL-12 production upon TLR activation was detected in the continuous treatment group when comparing to the single inoculation group and the germ-free control. In addition, continuous inoculation with L. kefiranofaciens M1 was found to ameliorate the symptoms of DSS-induced colitis in germ-free mice. However, L. kefiranofaciens M1 failed to colonize the host. Thus it would seem that L. kefiranofaciens M1 is likely to act directly on the host and not be involved in microbiota regulation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
This study determines the effect of the configuration of the magnetic field on the movement of gas bubbles that evolve from platinum electrodes. Oxygen and hydrogen bubbles respectively evolve from ...the surface of the anode and cathode and behave differently in the presence of a magnetic field due to their paramagnetic and diamagnetic characteristics. A magnetic field perpendicular to the surface of the horizontal electrode causes the bubbles to revolve. Oxygen and hydrogen bubbles revolve in opposite directions to create a swirling flow and spread the bubbles between the electrodes, which increases conductivity and the effectiveness of electrolysis. For vertical electrodes under the influence of a parallel magnetic field, a horizontal Lorentz force effectively detaches the bubbles and increases the conductivity and the effectiveness of electrolysis. However, if the layout of the electrodes and magnetic field results in upward or downward Lorentz forces that counter the buoyancy force, a sluggish flow in the duct inhibits the movement of the bubbles and decreases the conductivity and the charging performance. The results in this study determine the optimal layout for an electrode and a magnetic field to increase the conductivity and the effectiveness of water electrolysis, which is applicable to various fields including energy conversion, biotechnology, and magnetohydrodynamic thruster used in seawater.
Monocytes/macrophages are important in orchestrating inflammatory responses. However, knowledge of the long noncoding RNA (lncRNA) regulation of monocytic cell differentiation and diseases remains ...limited. We aimed to elucidate the role of the 17 kb lncRNA noncoding transcript in T cells (
) in monocyte functions. Knockdown and chromatin immunoprecipitation (ChIP) assays in THP-1 cells (human monocytic leukemia cell line) revealed that
is regulated by the monocyte key transcription factor C/EBPβ and that it binds to the promoter of nearby gene
via hnRNP-U. Overexpression of
in THP-1 cells resulted in cell cycle G1 arrest, differentiation into macrophages, a marked increase in
and
mRNA levels, and upregulation of the costimulatory molecules. In contrast to the downregulated
observed in lipopolysaccharide (LPS)-treated THP-1 cells, the
axis was found to be hyperactivated in peripheral blood mononuclear cells (PBMCs) of first-time diagnosed untreated early rheumatoid arthritis (RA) patients, and their gene expression levels decreased markedly after treatment. Higher initial
expression levels were associated with a trend of higher disease activity DAS28 scores. In conclusion, our study suggests that the lncRNA
is a regulator of inflammation in monocytes, and its activation participates in monocyte/macrophage differentiation and the pathogenesis of RA.
Extracellular particles (EPs) including extracellular vesicles (EVs) and exomeres play significant roles in diseases and therapeutic applications. However, their spatiotemporal dynamics in vivo have ...remained largely unresolved in detail due to the lack of a suitable method. Therefore, a bioluminescence resonance energy transfer (BRET)‐based reporter, PalmGRET, is created to enable pan‐EP labeling ranging from exomeres (<50 nm) to small (<200 nm) and medium and large (>200 nm) EVs. PalmGRET emits robust, sustained signals and allows the visualization, tracking, and quantification of the EPs from whole animal to nanoscopic resolutions under different imaging modalities, including bioluminescence, BRET, and fluorescence. Using PalmGRET, it is shown that EPs released by lung metastatic hepatocellular carcinoma (HCC) exhibit lung tropism with varying distributions to other major organs in immunocompetent mice. It is further demonstrated that gene knockdown of lung‐tropic membrane proteins, solute carrier organic anion transporter family member 2A1, alanine aminopeptidase/Cd13, and chloride intracellular channel 1 decreases HCC‐EP distribution to the lungs and yields distinct biodistribution profiles. It is anticipated that EP‐specific imaging, quantitative assays, and detailed in vivo characterization are a starting point for more accurate and comprehensive in vivo models of EP biology and therapeutic design.
PalmGRET, a bioluminescence resonance energy transfer (BRET)‐based reporter for extracellular particles (EPs), enables pan‐EP labeling, including extracellular vesicles and exomeres. PalmGRET allows accurate visualization, tracking, and quantification of EPs from whole animal to nanoscopic resolutions under different imaging modalities, including bioluminescence, BRET, and fluorescence. Using PalmGRET, lung‐tropic EP proteins are identified and dynamically altered biodistributions are revealed under redirected tropism.
Aims
To synthesise and evaluate the effectiveness of virtual reality interventions in preoperative children.
Background
Children consider operations as a predictable threat and stressful event. ...Children's anxiety before an operation increases as the time draws closer. Children could understand the operating room environment and process before the operation using virtual reality, which may reduce their anxiety before an operation.
Design
A systematic review and meta‐analysis of randomised controlled trials following the Cochrane method were conducted.
Method
CINAHL, Cochrane Library, Embase, Joanna Briggs Institute, MEDLINE and PubMed databases were searched for randomised controlled trials published before February 2021. A random‐effects model meta‐analysis to calculate pooled prevalence and 95% confidence intervals was performed. Conduction of the review adheres to the PRISMA checklist.
Results
Of 257 articles screened, six interventions involving 529 participants aged 4–12 years were included in the analysis. All study evidence levels were B2/Level 2, the quality was medium to high on the modified Jadad scale, with a low risk of bias. The results revealed that virtual reality significantly reduced preoperative anxiety in children (SMD: −0.91, 95% CI: −1.43 to −0.39, p = .0006). Furthermore, virtual reality significantly improved children's compliance with anaesthesia (SMD: 3.49, 95% CI: 1.32 to 9.21, p = .01).
Conclusion
Children who used virtual reality before an operation felt more familiar with the operating room environment and understood the preoperative preparation procedures. Virtual reality effectively reduced children's anxiety and improved their compliance with anaesthesia.
Relevance to clinical practice
This systematic review and meta‐analysis investigated the effect of virtual reality on preoperative anxiety in children and the findings supported its positive effects. The results could provide a reference for incorporating virtual reality into preoperative preparation guidelines.
Cancer stem cells (CSCs) are a promising target for treating cancer, yet how CSC plasticity is maintained in vivo is unclear and is difficult to study in vitro. Here we establish a sustainable ...primary culture of Oct3/4(+)/Nanog(+) lung CSCs fed with CD90(+) cancer-associated fibroblasts (CAFs) to further advance our knowledge of preserving stem cells in the tumour microenvironment. Using transcriptomics we identify the paracrine network by which CAFs enrich CSCs through de-differentiation and reacquisition of stem cell-like properties. Specifically, we find that IGF1R signalling activation in cancer cells in the presence of CAFs expressing IGF-II can induce Nanog expression and promote stemness. Moreover, this paracrine signalling predicts overall and relapse-free survival in stage I non-small cell lung cancer (NSCLC) patients. IGF-II/IGF1R signalling blockade inhibits Nanog expression and attenuates cancer stem cell features. Our data demonstrate that CAFs constitute a supporting niche for cancer stemness, and targeting this paracrine signalling may present a new therapeutic strategy for NSCLC.
Lung cancer in East Asia is characterized by a high percentage of never-smokers, early onset and predominant EGFR mutations. To illuminate the molecular phenotype of this demographically distinct ...disease, we performed a deep comprehensive proteogenomic study on a prospectively collected cohort in Taiwan, representing early stage, predominantly female, non-smoking lung adenocarcinoma. Integrated genomic, proteomic, and phosphoproteomic analysis delineated the demographically distinct molecular attributes and hallmarks of tumor progression. Mutational signature analysis revealed age- and gender-related mutagenesis mechanisms, characterized by high prevalence of APOBEC mutational signature in younger females and over-representation of environmental carcinogen-like mutational signatures in older females. A proteomics-informed classification distinguished the clinical characteristics of early stage patients with EGFR mutations. Furthermore, integrated protein network analysis revealed the cellular remodeling underpinning clinical trajectories and nominated candidate biomarkers for patient stratification and therapeutic intervention. This multi-omic molecular architecture may help develop strategies for management of early stage never-smoker lung adenocarcinoma.
Display omitted
•First deep proteogenomic landscape of non-smoking lung adenocarcinoma in East Asia•Identified age, sex-related endogenous, and environmental carcinogen mutagenic processes•Proteome-informed classification distinguished clinical features within early stages•Protein networks identified tumorigenesis hallmarks, biomarkers, and druggable targets
Deep proteogenomic landscape of early stage lung adenocarcinoma in a cohort of mostly non-smokers reveals unique drivers and biomarkers, as well as gender-associated mutagenesis.
Precision therapy for lung cancer requires comprehensive genomic analyses. Specific effects of targeted therapies have been reported in Asia populations, including Taiwanese, but genomic studies have ...rarely been performed in these populations.
We enrolled 72 patients with non-small cell lung cancer, of whom 61 had adenocarcinoma, 10 had squamous cell carcinoma, and 1 had combined adenocarcinoma and squamous cell carcinoma. Whole-exome or targeted gene sequencing was performed. To identify trunk mutations, we performed whole-exome sequencing in two tumor regions in four patients.
Nineteen known driver mutations in EGFR, PIK3CA, KRAS, CTNNB1, and MET were identified in 34 of the 72 tumors evaluated (47.22%). A comparison with the Cancer Genome Atlas dataset showed that EGFR was mutated at a much higher frequency in our cohort than in Caucasians, whereas KRAS and TP53 mutations were found in only 5.56% and 25% of our Taiwanese patients, respectively. We also identified new mutations in ARID1A, ARID2, CDK12, CHEK2, GNAS, H3F3A, KDM6A, KMT2C, NOTCH1, RB1, RBM10, RUNX1, SETD2, SF3B1, SMARCA4, THRAP3, TP53, and ZMYM2. Moreover, all ClinVar pathogenic variants were trunk mutations present in two regions of a tumor. RNA sequencing revealed that the trunk or branch genes were expressed at similar levels among different tumor regions.
We identified novel variants potentially associated with lung cancer tumorigenesis. The specific mutation pattern in Taiwanese patients with non-small cell lung cancer may influence targeted therapies.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
PDF
