Plasma and urine proteomics and gut microbiota analysis reveal potential factors affecting COVID-19 vaccination response.

The efficacy of COVID-19 vaccination relies on the induction of neutralizing antibodies, which can vary among vaccine recipients. In this study, we investigated the potential factors affecting the neutralizing antibody response by combining plasma and urine proteomics and gut microbiota analysis. We found that activation of the LXR/FXR pathway in plasma was associated with the production of ACE2-RBD-inhibiting antibodies, while urine proteins related to complement system, acute phase response signaling, LXR/FXR, and STAT3 pathways were correlated with neutralizing antibody production. Moreover, we observed a correlation between the gut microbiota and plasma and urine proteins, as well as the vaccination response. Based on the above data, we built a predictive model for vaccination response (AUC = 0.85). Our study provides insights into characteristic plasma and urine proteins and gut microbiota associated with the ACE2-RBD-inhibiting antibodies, which could benefit our understanding of the host response to COVID-19 vaccination.

RNF112-mediated FOXM1 ubiquitination suppresses the proliferation and invasion of gastric cancer.

Forkhead box M1 (FOXM1) plays a critical role in development physiologically and tumorigenesis pathologically. However, insufficient efforts have been dedicated to exploring the regulation, in particular the degradation of FOXM1. Here, the ON-TARGETplus siRNA library targeting E3 ligases was used to screen potential candidates to repress FOXM1. Of note, mechanism study revealed that RNF112 directly ubiquitinates FOXM1 in gastric cancer, resulting in a decreased FOXM1 transcriptional network and suppressing the proliferation and invasion of gastric cancer. Interestingly, the well-established small-molecule compound RCM-1 significantly enhanced the interaction between RNF112 and FOXM1, which further promoted FOXM1 ubiquitination and subsequently exerted promising anticancer effects in vitro and in vivo. Altogether, we demonstrate that RNF112 suppresses gastric cancer progression by ubiquitinating FOXM1 and highlight the RNF112/FOXM1 axis serves as both prognosis biomarker and therapeutic target in gastric cancer.

FOXM1 increases hTERT protein stability and indicates poor prognosis in gastric cancer.

Gastric cancer is one of most lethal diseases across the world. However, the underlying mechanism of gastric cancer carcinogenesis and development is still not fully known. Forkhead box M1 (FOXM1) belongs to the FOX family and has crucial roles in transactivation of multiple oncogenes in several cancer types, including gastric cancer. Recent studies have also shown the non-transcriptional function of FOXM1 via protein-protein interactions. Human telomerase reverse transcriptase (hTERT) is the core subunit of telomerase that facilitates cancer initiation and progression by maintaining cell immortalization, promoting cell proliferation and inhibiting cell apoptosis. However, the relationship between FOXM1 and hTERT in gastric cancer is still unclear. In our study, we found that FOXM1 and hTERT were convergent to the cell cycle-related pathways and they were positively related with advanced gastric cancer stages and poor outcomes. Simultaneous high levels of FOXM1 and hTERT predicted the worst prognosis. FOXM1 could increase hTERT protein rather than mRNA levels in a non-transcriptional manner. Mechanistically, FOXM1 interrupted the interaction between the E3 ligase MKRN1 and hTERT and decreased hTERT protein degradation. Further studies revealed that FOXM1 interacted with hTERT through its DNA-binding domain (DBD) region. Finally, we found that hTERT played important roles in FOXM1-mediated activation of the Wnt/ß-catenin pathway to promote gastric cancer cell proliferation. Taken together, we found a novel non-classical function of FOXM1 to increase hTERT protein stability. Targeting the FOXM1-hTERT pathway may be a potential therapeutic strategy in treating gastric cancer.

Helicobacter pylori and unignorable extragastric diseases: Mechanism and implications.

Considered as the most popular pathogen worldwide, Helicobacter pylori is intensively associated with diverse gastric diseases, including gastric ulcers, chronic progressive gastritis, and gastric cancer. Aside from its pathogenic effect on gastric diseases, growing evidences reveal that H. pylori may be related to numerous extragastric diseases. In this article, we reviewed recent studies and systematically elucidated that H. pylori may interfere with many biological processes outside the stomach and influence the occurrence of various extragastric diseases. Many epidemiological studies have indicated that H. pylori plays a pathogenic role in COVID-19, atherosclerosis, hyperemesis gravidarum and several other extragastric diseases, while the effect of H. pylori is currently under investigation in gastroesophageal reflux disease, asthma, and inflammatory bowel disease. Moreover, we also summarized the possible pathogenic mechanisms of H. pylori that may be related to chronic systemic inflammation and molecular mimicker. Taken together, this review provides a new perspective on the role of H. pylori in extragastric diseases and explores the possible mechanisms, which may help guide clinical treatment.

Helicobacter pylori infection induces stem cell-like properties in Correa cascade of gastric cancer.

Gastric cancer (GC) is the fourth leading cause of cancer-related death. Its poor prognosis is attributed to unclear pathogenesis. Currently, the most widely accepted model for elucidating the mechanism of GC is the Correa cascade, which covers several histological lesions of the gastric mucosa. GC stem cells (CSCs) are crucial for oncogenesis in the Correa cascade and GC progression. As Helicobacter pylori (H. pylori) is the etiological factor in the Correa cascade, growing evidence suggests that enhancement of gastric stem cell-like properties and increase in CSCs correlate with H. pylori infection. In this paper, we review recent studies that present pathogenic mechanisms by which H. pylori induces gastric stem cell-like properties and CSCs, which may supplement the existing Correa model of GC. First, the dysfunction of developmental signaling pathways associated with H. pylori infection leads to the enhancement of gastric stemness. Second, H. pylori infection promotes alteration of the gastric mucosal microenvironment. In addition, epithelial-mesenchymal transition (EMT) may contribute to H. pylori-induced gastric stemness. Taken together, understanding these pathogeneses will provide potential therapeutic targets for the treatment of CSCs and malignant GC in H. pylori induced-Correa cascade of GC.

Proteolysis-targeting chimeras: A promising technique in cancer therapy for gaining insights into tumor development.

Proteolysis-targeting chimeras (PROTACs) are small molecules that specifically link E3 ubiquitin ligases to proteins of interest to mediate targeted ubiquitination and degradation. PROTACs are advantageous since they can target undruggable proteins with multiple domains, particularly those with smooth surfaces that lack a common binding domain for small-molecule inhibitors (SMIs). This review provides an overview of PROTAC technology and third-generation PROTAC development. We focused on designing and executing the most recent clinical trials involving PROTACs in cancer therapy. Additionally, we summarized novel findings regarding the mechanisms and signaling pathways involved in cancer development, such as the scaffolding function of certain proteins ignored by traditional SMIs and several recognized oncoproteins that participate in novel signaling pathways. We also discussed strategies for enhancing PROTAC antitumor activity and specificity.

Design of novel functionalized collagen-chitosan-MBG scaffolds for enhancing osteoblast differentiation in BMSCs.

Collagen and chitosan are two different kinds of natural biodegradable polymers commonly used in the regeneration of bone defects. Mesoporous bioactive glass (MBG) is a type of favorable bone filler which can effectively constitute an enlarged microenvironment to facilitate an exchange of important factors between the cells and scaffolds. Here we prepared a collagen-chitosan-MBG (C-C-MBG) scaffold which displayed significantly increased proliferation, differentiation and mineralization in bone mesenchymal stem cells (BMSCs). Additionally, we found that the scaffold can stimulate extra-cellular signal regulated kinase 1/2 (Erk1/2) activated Runx2 pathway, which is the predominant signaling pathway involved in osteoblast differentiation. Consistently, we observed that the scaffold can markedly enhance the expression ofType I collagen, Osteopontin(Opn), andRunx2, which are important osteoblastic marker genes implicated in the process of osteoblast differentiation. Therefore, we conclude that the composite scaffold can significantly promote the differentiation of BMSCs into osteoblasts by activating Erk1/2-Runx2 pathway. Our finding thereby implies that the C-C-MBG scaffold can possibly act as a potential biomaterial in the bone regeneration.

[Moxibustion inhibits growth of tumor by down-regulating expression of FGFR1 and VEGFR2 in mice with sarcoma].

OBJECTIVE: To observe the effect of moxibustion on the growth of tumor and expression of fibroblast growth factor receptor 1 (FGFR1) and vascular endothelial cell growth factor receptor 2 (VEGFR2) in mice with sarcoma, so as to explore its mechanisms underlying inhibiting sarcoma growth. METHODS: C57BL/6J mice (half male and half female) were inoculated with S180 sarcoma cells to form transplanted tumors, and divided into model control, medication and moxibustion groups, with 10 mice in each group. Moxibustion was applied to the transplanted tumor directly for 10 min, once a day for 14 days. After the treatment, Luminex liquid suspension chip was used to detect the contents of serum vascular endothelial growth factor (VEGF), FGFR1 and VEGFR2. The weight of the transplanted tumor was measured, and the expression of VEGF in the transplanted tumor was detected by immunohistochemistry, and the expression of FGFR1 and VEGFR2 mRNAs in the transplanted tumor was detected by fluorescence in situ hybridization. RESULTS: The tumor weight, VEGF immunoactivity, serum VEGF, VEGFR2 and FGFR1 contents, and expression levels of VEGFR2 and FGFR1 mRNAs in the transplanted tumor were significantly lower in the moxibustion group than in the model group (P<0.001, P<0.01, P<0.05). Compared with the model group, the tumor weight was remarkably lower in the medication group (P<0.001). Compared with the medication group, th VEGF immunoactivity and the contents of serum VEGF, VEGFR2 and FGFR1 were significantly lower in the moxibustion group （P<0.01, P<0.05）. H.E. staining showed a large number of red blood cells were observed in the microenvironment of the transplanted tumor in the moxibustion group rather than in the medication group. CONCLUSION: Moxibustion can inhibit the growth of tumor in mice with sarcoma, which may be related to its function in reducing the expression of FGFR1 and VEGFR2 to inhibit angiogenesis.

Picosecond slab regenerative amplifier using a large fundamental mode stable-unstable hybrid cavity.

Slab gain media with large aspect ratios were difficult to be adopted in ultrafast regenerative amplifiers (RAs) due to the obstacle of mode matching with the seed beam. We proposed that an unstable cavity could be employed to solve this difficulty by taking the advantage of its large fundamental mode volume. In this way, an Nd:YVO4 slab-based picosecond RA has been successfully demonstrated using a stable-unstable hybrid cavity. The maximum average output power of 10.5 W was achieved at the repetition rate of 10 kHz. The beam quality factor M2 was measured to be 1.54 in the stable direction and 2.26 in the unstable direction.

Novel strategies for enhancing shotgun lipidomics for comprehensive analysis of cellular lipidomes.

Shotgun lipidomics is one of the most powerful tools in analysis of cellular lipidomes in lipidomics, which directly analyzes lipids from lipid extracts of diverse biological samples with high accuracy/precision. However, despite its great advances in high throughput analysis of cellular lipidomes, low coverage of poorly ionized lipids, especially those species in very low abundance, and some types of isomers within complex lipid extracts by shotgun lipidomics remains a huge challenge. In the past few years, many strategies have been developed to enhance shotgun lipidomics for comprehensive analysis of lipid species. Chemical derivatization represents one of the most attractive and effective strategies, already receiving considerable attention. This review focuses on novel advanced derivatization strategies for enhancing shotgun lipidomics. It is anticipated that with the development of enhanced strategies, shotgun lipidomics can make greater contributions to biological and biomedical research.

Shotgun Lipidomics Revealed Altered Profiles of Serum Lipids in Systemic Lupus Erythematosus Closely Associated with Disease Activity.

The pathogenesis of systemic lupus erythematosus (SLE) remains elusive. It appears that serum lipid metabolism is aberrant in SLE patients. Determination of lipid profiles in the serum of SLE patients may provide insights into the underlying mechanism(s) leading to SLE and may discover potential biomarkers for early diagnosis of SLE. This study aimed to identify and quantify the profile of serum lipids in SLE patients (N = 30) with our powerful multi-dimensional mass spectrometry-based shotgun lipidomics platform. Multivariate analysis in the form of partial least squares-discriminate analysis was performed, and the associations between the changed lipids with cytokines and SLE disease activity index (SLEDAI) were analyzed using a multiple regression method. The results of this study indicated that the composition of lipid species including diacyl phosphatidylethanolamine (dPE) (16:0/18:2, 18:0/18:2, 16:0/22:6, 18:0/20:4, and 18:0/22:6), 18:2 lysoPC (LPC), and ceramide (N22:0 and N24:1) was significantly altered in SLE patients with p < 0.05 and variable importance of the projection (VIP) > 1 in partial least squares-discriminate analysis (PLS-DA). There existed significant associations between IL-10, and both 18:0/18:2 and 16:0/22:6 dPE species with p < 0.0001 and predicting 85.7 and 95.8% of the variability of IL-10 levels, respectively. All the altered lipid species could obviously predict IL-10 levels with F (8, 21) = 3.729, p = 0.007, and R² = 0.766. There was also a significant correlation between the SLEDAI score and 18:0/18:2 dPE (p = 0.031) with explaining 22.6% of the variability of SLEDAI score. Therefore, the panel of changed compositions of dPE and ceramide species may serve as additional biomarkers for early diagnosis and/or prognosis of SLE.

30.5-µJ, 10-kHz, picosecond optical parametric oscillator pumped synchronously and intracavity by a regenerative amplifier.

We have proposed a novel approach to realize a high-energy ultrafast optical parametric oscillator (OPO) by intracavity pumping in a regenerative amplifier. In this way, we have experimentally demonstrated an unprecedented pulse energy of 30.5 µJ from a 1.5-µm singly resonant synchronously pumped OPO at a pulse repetition rate of 10 kHz with a pulse width of 7.0 ps. To the best of our knowledge, this is the highest pulse energy from an ultrafast laser OPO.

Etiology and antimicrobial resistance patterns in pediatric urinary tract infection.

BACKGROUND: Urinary tract infection (UTI) is one of most common pediatric infections. The aim of this study was to investigate the etiology and antimicrobial resistance patterns in children hospitalized at Children's Hospital of Nanjing Medical University. METHODS: We conducted a retrospective, descriptive study of all UTI from 1 January 2013 to 30 November 2016 in children discharged from Nanjing Children's Hospital. The isolated pathogens and their resistance patterns were examined using midstream urine culture. RESULTS: A total of 2,316 children with UTI were included in the study. The occurrence rates of isolated pathogens were as follows: Enterococcus spp., 35.15%; Escherichia coli, 22.32%; Staphylococcus aureus spp., 7.73%; Streptococcus spp., 7.51%; and Klebsiella spp., 6.95%. Uropathogens had a low susceptibility to linezolid (3.47%), vancomycin (0.92%), imipenem (5.74%), and amikacin (3.17%), but they had a high susceptibility to erythromycin (90.52%), penicillin G (74.01%), cefotaxime (71.41%), cefazolin (73.41%), cefuroxime (72.52%), and aztreonam (70.11%). CONCLUSIONS: There is high antibiotic resistance in hospitalized children with UTI. Susceptibility testing should be carried out on all clinical isolates, and the empirical antibiotic treatment should be altered accordingly.

Pulse width adjustable Q-switched cavity dumped laser by rotating a quarter-wave plate and a Pockels cell.

A pulse width adjustable 1064 nm Q-switched cavity dumped Nd:YVO4 laser was realized for the first time, to the best of our knowledge, by rotating an intracavity quarter-wave plate (QWP) and a Pockels cell (PC). The pulse width adjustment range was 4.8-7.8 ns with a constant output power of 3.6 W, and it reached 4.8-13.5 ns for a lower output power of 1.3 W. The pulse width was dependent mostly on the rotating angle of the QWP and PC, but independent of the gain and pulse repetition rate.