Transcriptome-wide 1-methyladenosine functional profiling of messenger RNA and long non-coding RNA in bladder cancer.

Introduction: Post-transcriptional RNA modifications are crucial regulators of tumor development and progression. In many biological processes, N1-methyladenosine (m1A) plays a key role. However, little is known about the links between chemical modifications of messenger RNAs (mRNAs) and long noncoding RNAs (lncRNAs) and their function in bladder cancer (BLCA). Methods: Methylated RNA immunoprecipitation sequencing and RNA sequencing were performed to profile mRNA and lncRNA m1A methylation and expression in BLCA cells, with or without stable knockdown of the m1A methyltransferase tRNA methyltransferase 61A (TRMT61A). Results: The analysis of differentially methylated gene sites identified 16,941 peaks, 6,698 mRNAs, and 10,243 lncRNAs in the two groups. Gene ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway analyses of the differentially methylated and expressed transcripts showed that m1A-regulated transcripts were mainly related to protein binding and signaling pathways in cancer. In addition, the differentially genes were identified that were also differentially m1A-modified and identified 14 mRNAs and 19 lncRNAs. Next, these mRNAs and lncRNAs were used to construct a lncRNA-microRNA-mRNA competing endogenous RNA network, which included 118 miRNAs, 15 lncRNAs, and 8 mRNAs. Finally, the m1A-modified transcripts, SCN2B and ENST00000536140, which are highly expressed in BLCA tissues, were associated with decreased overall patient survival. Discussion: This study revealed substantially different amounts and distributions of m1A in BLCA after TRMT61A knockdown and predicted cellular functions in which m1A may be involved, providing evidence that implicates m1A mRNA and lncRNA epitranscriptomic regulation in BLCA tumorigenesis and progression.

Association between periodontal disease and osteoporosis in postmenopausal women: a protocol for systematic review and meta-analysis.

INTRODUCTION: Periodontal disease and osteoporosis are common chronic diseases, especially for the postmenopausal women. Several original studies explore the association, but there still controversial. Therefore, we will conduct this systematic review and meta-analysis to assess the association between periodontal disease and osteoporosis in postmenopausal women. METHODS AND ANALYSIS: This study adheres to the Preferred Reporting Items for Systematic Reviews and Meta-analyses for Protocols. We will systematically search Medline/PubMed, Embase, Cochrane Central Register of Controlled Trials, Web of Science and Scopus from inception to August 2021 to collect all relevant publications, with no restrictions on publication date or languages. Study selection, data extraction and risk of bias assessment will be conducted independently by two trained reviewers independently. The Cochrane's tool for assessing risk of bias, Newcastle-Ottawa Scale and Agency for Healthcare Research and Quality will be used for the risk of bias assessment. OR, HR and risk ratio with 95% CI were considered as the effect size for dichotomous outcomes, weighted mean difference with 95% CI were calculated as the effect size for continuous outcomes. Random-effects models will be used. Heterogeneity between studies will be assessed via the forest plot and I². Publication bias will detected by funnel plots, Begg's test and Egger's test. The subgroup analyses and sensitivity ananlyses will also be used to explore and interpret the heterogeneity. ETHICS AND DISSEMINATION: This study does not require ethical approval. We will disseminate our findings by publishing results in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42021225746.

Calcium channel blockers improve prognosis of patients with coronavirus disease 2019 and hypertension.

BACKGROUND: Hypertension is considered an important risk factor for the coronavirus disease 2019 (COVID-19). The commonly anti-hypertensive drugs are the renin-angiotensin-aldosterone system (RAAS) inhibitors, calcium channel blockers (CCBs), and beta-blockers. The association between commonly used anti-hypertensive medications and the clinical outcome of COVID-19 patients with hypertension has not been well studied. METHODS: We conducted a retrospective cohort study that included all patients admitted with COVID-19 to Huo Shen Shan Hospital and Guanggu District of the Maternal and Child Health Hospital of Hubei Province, Wuhan, China. Clinical and laboratory characteristics were extracted from electronic medical records. Hypertension and anti-hypertensive treatment were confirmed by medical history and clinical records. The primary clinical endpoint was all-cause mortality. Secondary endpoints included the rates of patients in common wards transferred to the intensive care unit and hospital stay duration. Logistic regression was used to explore the risk factors associated with mortality and prognosis. Propensity score matching was used to balance the confounders between different anti-hypertensive treatments. Kaplan-Meier curves were used to compare the cumulative recovery rate. Log-rank tests were performed to test for differences in Kaplan-Meier curves between different groups. RESULTS: Among 4569 hospitalized patients with COVID-19, 31.7% (1449/4569) had a history of hypertension. There were significant differences in mortality rates between hypertensive patients with CCBs (7/359) and those without (21/359) (1.95% vs. 5.85%, risk ratio [RR]: 0.32, 95% confidence interval [CI]: 0.13-0.76, χ2 = 7.61, P = 0.0058). After matching for confounders, the mortality rates were similar between the RAAS inhibitor (4/236) and non-RAAS inhibitor (9/236) cohorts (1.69% vs. 3.81%, RR: 0.43, 95% CI: 0.13-1.43, χ2 = 1.98, P = 0.1596). Hypertensive patients with beta-blockers (13/340) showed no statistical difference in mortality compared with those without (11/340) (3.82% vs. 3.24%, RR: 1.19, 95% CI: 0.53-2.69, χ2 = 0.17, P = 0.6777). CONCLUSIONS: In our study, we did not find any positive or negative effects of RAAS inhibitors or beta-blockers in COVID-19 patients with hypertension, while CCBs could improve prognosis.

Establish a Scoring Model for High-Risk Population of Gastric Cancer and Study on the Pattern of Opportunistic Screening.

OBJECTIVE: To investigate and study the related risk factors of gastric cancer (GC) patients, to establish a high-risk scoring model of GC by multiple logistic regression analysis, and to explore the establishment of a GC screening mode with clinical opportunistic screening as the main method, and by using the pattern of opportunistic screening to establish the screening of high-risk GC patients and the choice of screening methods in the clinical outpatient work. METHODS: Collected the epidemiological questionnaire of 99 GC cases and 284 non-GC patients (other chronic gastric diseases and normal) diagnosed by the General Hospital of Ningxia Medical University from October 2017 to March 2019. Serum pepsinogen (PG) levels were measured by enzyme-linked immunosorbent assay (ELISA) and confirmed Helicobacter pylori (Hp) infection in gastric mucosa tissues by Giemsa staining. Determined the high-risk factors and established a scoring model through unconditional logistic regression model analysis, and the ROC curve determined the cut-off value. Then, we followed up 26 patients of nongastric cancer patients constituted a validation group, which validated the model. RESULTS: The high-risk factors of GC included age ≥ 55, male, drinking cellar or well water, family history of GC, Hp infection, PGI ≤ 43.6 µg/L, and PGI/PGII ≤ 2.1. Established the high-risk model: Y = A × age + 30 × gender + 30 × drinking water + 30 × Hp infection + 50 × family history of GC + B × PG level. The ROC curve determined that the cut-off value for high-risk GC population was ≥155, and the area under the curve (AUC) was 0.875, the sensitivity and specificity were 87.9% and 71.5%. CONCLUSIONS: According to the risk factors of GC, using statistical methods can establish a high-risk scoring model of GC, and the score ≥ 155 is divided into the screening cut-off value for high-risk GC population. Using this model for clinical outpatient GC screening is cost-effective and has high sensitivity and specificity.

Efficacy and safety of tocilizumab in COVID-19 patients.

In this retrospective study we assessed the efficacy and safety of tocilizumab in patients with critical or severe coronavirus disease 2019 (COVID-19). We enrolled 181 patients admitted to Huoshenshan Hospital (Wuhan, China) with confirmed COVID-19 between January 2020 and February 2020. Ninety-two patients were treated with tocilizumab, and 89 patients were treated conventionally. We analyzed the clinical manifestations, changes in CT scan images, and laboratory tests before and after tocilizumab treatment, and compared these results with the conventionally treated group. A significant reduction in the level of C-reactive protein was observed 1 week after tocilizumab administration. In some cases this meant the end of the IL-6-related cytokine storm. In addition, tocilizumab relieved fever, cough, and shortness of breath with no reported adverse drug reactions. These findings suggest tocilizumab improves clinical outcomes and is effective for treatment of patients with critical or severe COVID-19. However, future clinical trials are needed to better understand the impact of tocilizumab interference with IL-6 and provide a therapeutic strategy for treatment of COVID-19.

Soft Porous Blade Printing of Nonfullerene Organic Solar Cells.

Developing scalable and robust processing methods with low material waste remains a challenge for organic solar cells (OSCs) to become a practical renewable energy source. Here, we present a novel low-cost processing approach termed as soft porous blade printing (SPBP), which uses a layer of soft porous material such as filter paper as the printing blade. The inherent porous microstructure of the blade offers high shear rates that facilitate the alignment, crystallization, and orientation of active materials during printing. Moreover, by eliminating the suspended liquid meniscus, SPBP relaxes the stringent requirement of gap control and enables continuous ink delivery for uninterrupted film fabrication with adjustable thickness. Higher photovoltaic performances are achieved in the SPBP-printed OSCs than those of the spin-coated counterparts for two nonfullerene-acceptor active-layer systems (Y6:PM6 and PTQ10:IDIC). Y6:PM6 cells printed by SPBP without any additive exhibit power conversion efficiencies up to 14.75%, which is among the highest reported to date for non-spin-coated OSCs.

Inhibition of the ALDH18A1-MYCN positive feedback loop attenuates MYCN-amplified neuroblastoma growth.

MYCN-amplified neuroblastoma (NB) is characterized by poor prognosis, and directly targeting MYCN has proven challenging. Here, we showed that aldehyde dehydrogenase family 18 member A1 (ALDH18A1) exerts profound impacts on the proliferation, self-renewal, and tumorigenicity of NB cells and is a potential risk factor in patients with NB, especially those with MYCN amplification. Mechanistic studies revealed that ALDH18A1 could both transcriptionally and posttranscriptionally regulate MYCN expression, with MYCN reciprocally transactivating ALDH18A1 and thus forming a positive feedback loop. Using molecular docking and screening, we identified an ALDH18A1-specific inhibitor, YG1702, and demonstrated that pharmacological inhibition of ALDH18A1 was sufficient to induce a less proliferative phenotype and confer tumor regression and prolonged survival in NB xenograft models, providing therapeutic insights into the disruption of this reciprocal regulatory loop in MYCN-amplified NB.

Author Correction: Invasion of white matter tracts by glioma stem cells is regulated by a NOTCH1-SOX2 positive-feedback loop.

The original and corrected figures are shown in the accompanying Author Correction.

Invasion of white matter tracts by glioma stem cells is regulated by a NOTCH1-SOX2 positive-feedback loop.

Early invasive growth along specific anatomical structures, especially the white matter tract, is regarded as one of the main causes of poor therapeutic outcome of people with gliomas. We show that some glioma stem cells (GSCs) are preferentially located along white matter tracts, which exhibit a demyelinated phenotype, at the invasive frontier of glioma tissues. These GSCs are CD133+Notch1+, whereas the nerve fibers express the Notch ligand Jagged1. The Notch-induced transcription factor Sox9 promotes the transcription of SOX2 and the methylation level of the NOTCH1 promoter is attenuated by the upregulation of SOX2 to reinforce NOTCH1 expression in GSCs. This positive-feedback loop in a cohort of glioma subjects is correlated with a poor prognosis. Inhibition of Notch signaling attenuates the white-matter-tract tropism of GSCs. These findings provide evidence indicating that the NOTCH1-SOX2 positive-feedback loop controls GSC invasion along white matter tracts.

Connexin 43 C-terminus directly inhibits the hyperphosphorylation of Akt/ERK through protein-protein interactions in glioblastoma.

Although the deregulation of epidermal growth factor receptor (EGFR) is one of the most common molecular mechanisms of glioblastoma (GBM) pathogenesis, the efficacy of anti-EGFR therapy is limited. Additionally, response to anti-EGFR therapy is not solely dependent on EGFR expression and is more promising in patients with reduced activity of EGFR downstream signaling pathways. Thus, there is considerable interest in identifying the compensatory regulatory factors of the EGFR signaling pathway to improve the efficacy of anti-EGFR therapies for GBM. In this study, we confirmed the low efficacy of EGFR inhibitors in GBM patients by meta-analysis. We then identified a negative correlation between connexin 43 (Cx43) expression and Akt/ERK activation, which was caused by the direct interactions between Akt/ERK and Cx43. By comparing the interactions between Akt/ERK and Cx43 using a series of truncated and mutated Cx43 variants, we revealed that the residues T286/A305/Q308/Y313 and S272/S273 at the carboxy terminus of Cx43 are critical for its binding with Akt and ERK, respectively. In addition, Kaplan-Meier survival analysis using data from The Cancer Genome Atlas datasets indicated that the expression of Cx43 significantly improved the prognosis of GBM patients who express EGFR. Together, our results suggested that Cx43 acts as an inhibitory regulator of the activation of growth factor receptor downstream signaling pathways, indicating the potential of Cx43 as a marker for predicting the efficacy of EGFR inhibitor treatments for GBM. Targeting the interaction between the carboxy terminus of Cx43 and Akt/ERK could be an effective therapeutic strategy against GBM.

Targeting different domains of gap junction protein to control malignant glioma.

A rational treatment strategy for glioma, the most common primary central nervous system tumor, should focus on early invasive growth and resistance to current therapeutics. Connexin 43 (Cx43), a gap junction protein, plays important roles not only in the development of the central nervous system and but also in the progression of glioma. The different structural domains of Cx43, including extracellular loops, transmembrane domains, and an intracellular carboxyl terminal, have distinct functions in the invasion and proliferation of gliomas. Targeting these domains of Cx43, which is expressed in distinct patterns in the heterogeneous glioma cell population, can inhibit tumor cell invasion and new tumor formation. Thus, this review summarizes the structural characteristics of Cx43, the effects of regulating different Cx43 domains on the biological characteristics of glioma cells, intervention strategies targeting different domains of Cx43, and future research directions.

ALDH1A3, a metabolic target for cancer diagnosis and therapy.

Metabolism reprogramming has been linked with the initiation, metastasis, and recurrence of cancer. The aldehyde dehydrogenase (ALDH) family is the most important enzyme system for aldehyde metabolism. The human ALDH family is composed of 19 members. ALDH1A3 participates in various physiological processes in human cells by oxidizing all-trans-retinal to retinoic acid. ALDH1A3 expression is regulated by many factors, and it is associated with the development, progression, and prognosis of cancers. In addition, ALDH1A3 influences a diverse range of biological characteristics within cancer stem cells and can act as a marker for these cells. Thus, growing evidence indicates that ALDH1A3 has the potential to be used as a target for cancer diagnosis and therapy.

Chryseobacterium flavum sp. nov., isolated from polluted soil.

A Gram-negative, non-motile, rod-shaped bacterial strain, designated CW-E 2(T), was isolated from a polluted soil sample collected from Jiangsu Province, China. A taxonomic study of the isolate, including phylogenetic analysis based on 16S rRNA gene sequences and phenotypic characteristics, was carried out. The predominant menaquinone was MK-6 and the major fatty acids were i-C(15 : 0), i-C(17 : 0) 3-OH, i-C(17 : 1) omega 9c and summed feature 4. The G+C content of the DNA was 37.2 mol%. Based on phenotypic and genotypic characteristics, strain CW-E 2(T) represents a novel species of the genus Chryseobacterium for which the name Chryseobacterium flavum sp. nov. is proposed. The type strain is CW-E 2(T) (=KCTC 12877(T)=CCTCC AB 206147(T)).

Marinobacter gudaonensis sp. nov., isolated from an oil-polluted saline soil in a Chinese oilfield.

Two novel strains, SL014B61A(T) and SL014B11A, were isolated from an oil-polluted saline soil from Gudao in the coastal Shengli Oilfield, eastern China. Cells of strains SL014B61A(T) and SL014B11A were motile, Gram-negative and rod-shaped. Growth occurred at NaCl concentrations of between 0 and 15 % and at temperatures of between 10 and 45 degrees C. Strain SL014B61A(T) had Q9 as the major respiratory quinone and C16 : 0 (21.2 %), C18 : 1omega9c (20.3 %), C16 : 1omega7c (7.3 %) and C16 : 1omega9c (6.4 %) as predominant fatty acids. The G+C content of the DNA was 57.9 mol%. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain SL014B61A(T) belonged to the genus Marinobacter in the class Gammaproteobacteria. Strain SL014B61A(T) showed the highest 16S rRNA gene sequence similarity with Marinobacter bryozoorum (97.9 %) and showed 97.8 % sequence similarity to Marinobacter lipolyticus. DNA-DNA relatedness to the reference strains Marinobacter bryozoorum and Marinobacter lipolyticus was 35.5 % and 33.8 %, respectively. On the basis of these data, it is proposed that strains SL014B61A(T) and SL014B11A represent a novel species, Marinobacter gudaonensis sp. nov. The type strain is strain SL014B61A(T) (=DSM 18066(T)=LMG 23509(T)=CGMCC 1.6294(T)).

[Enhanced ammonia removal and microbial community structure analysis using bacterial quinone profile in ITFB].

Water quality during the start-up period was changed in order to enhance the later nitrifying ability of the internal-circulation three-phase bio-fluidized bed (ITFB). The experimental results showed that high N/C ratio and low feeding concentration of COD were two key conditions for enhancing the ammonia removal. After the enhanced start-up, an efficient removal efficiency of both COD and ammonia was achieved with HRT 2h when treating sanitary wastewater, the average ammonia removal rate was 74% , the ammonia concentration in effluent was lower than 10 mg/L. Bacterial quinone profile of the system was also analyzed. The results showed that after the enhanced start-up, the number of nitrifying bacteria, such as Nitrosomonas europaea, in the biofilm in ITFB was increased, and the number of gamma-Proteobacteria, such as Acinetobacter sp. and Pseudomonas sp., was decreased. the equitability of the quinones (EQ) fluctuated around 0.5 showed that the distribution of the microbial community in the biofilm changed little. UQ/MK ratio of all the samples was greater than 1 indicated that Gram-negative bacteria was the dominant bacteria in the system.