Esophageal cancer (ESCA) is the eighth most common cause of cancer-associated mortality in humans. An increasing number of studies have demonstrated that microRNAs (miRs) serve important roles in mediating tumor initiation and progression. miR-454-3p has been found to be involved in the development of various human malignancies; however, little is known about the role of miR-454-3p in esophageal cancer. In the present study, the protein and gene expression levels of miR-454-3p in ESCA tissues and cells were downregulated compared with adjacent normal tissues and normal human esophageal epithelial cells. Additionally, miR-454-3p downregulation resulted in improved survival rates in patients with ESCA, and miR-454-3p overexpression significantly suppressed cell proliferation, migration and invasion and promoted apoptosis in four ESCA cell lines (EC9706, ECA109, TE-1 and TE-8). It was found that miR-454-3p overexpression inhibited the expression of insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) at the protein and mRNA expression levels. Furthermore, it was demonstrated that miR-454-3p inhibited ESCA cell proliferation, migration and apoptosis by targeting IGF2BP1 via the ERK and AKT signaling pathways in a subcutaneous xenograft tumor mouse model. These results showed that miR-454-3p functioned as an important tumor suppressor in ESCA by targeting IGFBP1. Therefore, miR-454-3p may be a novel prognostic biomarker and therapeutic target for patients with ESCA.

Hypospadias is a common congenital genitourinary malformation characterized by ventral opening of the urethral meatus. As a member of the bone morphogenic protein antagonist family, GREM1 has been identified as associated with susceptibility to hypospadias in the European population. The present study was designed to elaborate on the mutual relationship between replicated single-nucleotide polymorphisms (SNPs) and hypospadias in Asia's largest case-control study in the Southern Han Chinese population involving 577 patients and 654 controls. Our results demonstrate that the GREM1 risk allele rs3743104[G] markedly increases the risk of mild/moderate and severe hypospadias (P<0.01, 0.28≤OR≤0.66). GTEx expression quantitative trait locus data revealed that the eQTL SNP rs3743104 has more associations of eQTL SNP rs3743104 and GREM1 targets in pituitary tissues. Additionally, Bioinformatics and Luciferase Assays show that miR-182 is identified as a suppressor for GREM1 expression, likely through regulation of its binding affinity to rs3743104 locus. In conclusion, the GREM1 risk allele rs3743104[G] increases hypospadias susceptibility in mild/moderate and severe cases among the southern Han population. rs3743104 regulates GREM1 expression by altering the binding affinity of miR-182 to their locus. Collectively, this study provides new evidence that GREM1 rs3743104 is associated with an increased risk of hypospadias. These findings provide a promising biomarker and merit further exploration.

Phage therapy represents a possible treatment option to cure infections caused by multidrug-resistant bacteria, including methicillin and vancomycin-resistant Staphylococcus aureus, to which most antibiotics have become ineffective. In the present study, we report the isolation and complete characterization of a novel phage named JD219 exhibiting a broad host range able to infect 61 of 138 clinical strains of S. aureus tested, which included MRSA strains as well. The phage JD419 exhibits a unique morphology with an elongated capsid and a flexible tail. To evaluate the potential of JD419 to be used as a therapeutic phage, we tested the ability of the phage particles to remain infectious after treatment exceeding physiological pH or temperature. The activity was retained at pH values of 6.0-8.0 and below 50°C. As phages can contain virulence genes, JD419's complete genome was sequenced. The 45509 bp genome is predicted to contain 65 ORFs, none of which show homology to any known virulence or antibiotic resistance genes. Genome analysis indicates that JD419 is a temperate phage, despite observing rapid replication and lysis of host strains. Following the recent advances in synthetic biology, JD419 can be modified by gene engineering to remove prophage-related genes, preventing potential lysogeny, in order to be deployed as a therapeutic phage.

Selective modulation of the heterotrimeric G protein α S subunit-coupled prostaglandin E2 (PGE2) receptor EP2 subtype is a promising therapeutic strategy for osteoporosis, ocular hypertension, neurodegenerative diseases, and cardiovascular disorders. Here, we report the cryo-electron microscopy structure of the EP2-Gs complex with its endogenous agonist PGE2 and two synthesized agonists, taprenepag and evatanepag (CP-533536). These structures revealed distinct features of EP2 within the EP receptor family in terms of its unconventional receptor activation and G protein coupling mechanisms, including activation in the absence of a typical W6.48 "toggle switch" and coupling to Gs via helix 8. Moreover, inspection of the agonist-bound EP2 structures uncovered key motifs governing ligand selectivity. Our study provides important knowledge for agonist recognition and activation mechanisms of EP2 and will facilitate the rational design of drugs targeting the PGE2 signaling system.

The National Chest Pain Center Accreditation Program (CHANGE) is the first hospital-based, multifaceted, nationwide quality improvement (QI) initiative, to monitor and improve the quality of the ST segment elevation myocardial infarction (STEMI) care in China. The QI initiatives, as implementation strategies, include a bundle of evidence-based interventions adapted for implementation in China. During the pandemic of coronavirus disease 2019 (COVID-19), fear of infection with severe acute respiratory syndrome coronavirus 2, national lockdowns, and altered health care priorities have highlighted the program's importance in improving STEMI care quality. This study aims to minimize the adverse impact of the COVID-19 pandemic on the quality of STEMI care, by developing interventions that optimize the QI initiatives, implementing and evaluating the optimized QI initiatives, and developing scale-up activities of the optimized QI initiatives in response to COVID-19 and other public health emergencies.

Background and Objective: An increasing number of epidemiological original studies suggested that long-term exposure to particulate matter (PM2.5 and PM10) could be associated with the risk of myocardial infarction (MI), but the results were inconsistent. We aimed to synthesized available cohort studies to identify the association between ambient air pollution (PM2.5 and PM10) and MI risk by a meta-analysis. Methods: PubMed and Embase were searched through September 2019 to identify studies that met predetermined inclusion criteria. Reference lists from retrieved articles were also reviewed. A random-effects model was used to calculate the pooled relative risk (RR) and 95% confidence intervals (CI). Results: Twenty-seven cohort studies involving 6,764,987 participants and 94,540 patients with MI were included in this systematic review. The pooled results showed that higher levels of ambient air pollution (PM2.5 and PM10) exposure were significantly associated with the risk of MI. The pooled relative risk (RR) for each 10-μg/m3 increment in PM2.5 and PM10 were 1.18 (95% CI: 1.11-1.26), and 1.03 (95% CI: 1.00-1.05), respectively. Exclusion of any single study did not materially alter the combined risk estimate. Conclusions: Integrated evidence from cohort studies supports the hypothesis that long-term exposure to PM2.5 and PM10 is a risk factor for MI.

Major societies provide differing guidance on management of Barrett's esophagus (BE), making standardization challenging.

Inflammatory breast cancer (IBC) has a highly invasive and metastatic phenotype. However, little is known about its genetic drivers. To address this, we report the largest cohort of whole-genome sequencing (WGS) of IBC cases.

Inherited predispositions to acute lymphoblastic leukemia have been well investigated in pediatric patients, but studies on adults, particularly Chinese patients, are limited. In this study, we conducted a genome-wide association study in 466 all-age Chinese patients with Acute lymphoblastic leukemia (ALL) and 1,466 non-ALL controls to estimate the impact of age on ALL susceptibility in the Chinese population. Among the 17 reported loci, 8 have been validated in pediatric and 1 in adult patients. The strongest association signal was identified at ARID5B locus and gradually decreased with age, while the signal at GATA3 exhibited the opposite trend and significantly impact on adult patients. With genome-wide approaches, germline variants at 2q14.3 rank as the top inherited predisposition to adult patients (e.g., rs73956024, P = 4.3 × 10-5) and separate the genetic risk of pediatric vs. adult patients (P = 3.6 × 10-6), whereas variants at 15q25.3 (e.g., rs11638062) have a similar impact on patients in different age groups (overall P = 2.9 × 10-7). Our analysis highlights the impact of age on genetic susceptibility to ALL in Chinese patients.

Site specific integration (SSI) expression systems offer robust means of generating highly productive and stable cell lines for traditional monoclonal antibodies. As complex modalities such as antibody-like molecules comprised of greater than two peptides become more prevalent, greater emphasis needs to be placed on the ability to produce appreciable quantities of the correct product of interest (POI). The ability to screen several transcript stoichiometries could play a large role in ensuring high amounts of the correct POI. Here we illustrate implementation of an SSI expression system with a single site of integration for development and production of a multi-chain, bi-specific molecule. A SSI vector with a single copy of all of the genes of interest was initially selected for stable Chinese hamster ovary transfection. While the resulting transfection pools generated low levels of the desired heterodimer, utilizing an intensive clone screen strategy, we were able to identify clones having significantly higher levels of POI. In-depth genotypic characterization of clones having the desirable phenotype revealed that a duplication of the light chain within the landing pad was responsible for producing the intended molecule. Retrospective transfection pool analysis using a vector configuration mimicking the transgene configuration found in the clones, as well as other vector configurations, yielded more favorable results with respect to % POI. Overall, the study demonstrated that despite the theoretical static nature of the SSI expression system, enough heterogeneity existed to yield clones having significantly different transgene phenotypes/genotypes and support production of a complex multi-chain molecule.

The aim of this study was to elucidate the prevalence of blaCTX-M-27-producing Escherichia coli and transmission mechanisms of blaCTX-M-27 from swine farms in China. A total of 333 E. coli isolates were collected from two farms from 2013 to 2016. Thirty-two CTX-M-27-positive E. coli were obtained, and all were multidrug-resistant. Pulsed field gel electrophoresis (PFGE) and multilocus sequence typing (MLST) profiles indicated a wide range of strain types that carried blaCTX-M-27, and the sequence type ST10 predominated. Conjugation, replicon typing, S1-PFGE and hybridization experiments confirmed that 28 out of 32 CTX-M-27 positive isolates carried blaCTX-M-27 genes on plasmids F18:A-:B10 (16) and F24:A-:B1 (12).The blaCTX-M-27 genes for 24 isolates were transmitted by plasmids with sizes ranging from 40 to 155 kb. A comparative analysis with blaCTX-M-27-plasmids indicated that the tra-trb region of F24:A-:B1 plasmids was destroyed by insertion of a complex region (eight isolates) and a novel structure containing blaCTX-M-27 in the F18:A-:B10 plasmids (12 isolates). The novel structure increased the stability of the blaCTX-M-27 gene in E. coli. This study indicated that the predominant vehicle for blaCTX-M-27 transmission has diversified over time and that control strategies to limit blaCTX-M-27 transmission in farm animals are necessary.

The brain is known to express many long noncoding RNAs (lncRNAs); however, whether and how these lncRNAs function in modulating synaptic stability remains unclear. Here, we report a cerebellum highly expressed lncRNA, Synage, regulating synaptic stability via at least two mechanisms. One is through the function of Synage as a sponge for the microRNA miR-325-3p, to regulate expression of the known cerebellar synapse organizer Cbln1. The other function is to serve as a scaffold for organizing the assembly of the LRP1-HSP90AA1-PSD-95 complex in PF-PC synapses. Although somewhat divergent in its mature mRNA sequence, the locus encoding Synage is positioned adjacent to the Cbln1 loci in mouse, rhesus macaque, and human, and Synage is highly expressed in the cerebella of all three species. Synage deletion causes a full-spectrum cerebellar ablation phenotype that proceeds from cerebellar atrophy, through neuron loss, on to synapse density reduction, synaptic vesicle loss, and finally to a reduction in synaptic activity during cerebellar development; these deficits are accompanied by motor dysfunction in adult mice, which can be rescued by AAV-mediated Synage overexpression from birth. Thus, our study demonstrates roles for the lncRNA Synage in regulating synaptic stability and function during cerebellar development.

Background: The prognosis of early cardia cancer and non-cardia cancer is still controversial. It is difficult to collect a large number of cases with complete information in clinical practice. Our study was aimed to identify the differences in clinicopathological characteristics and outcomes of early cardia gastric cancer and non-cardia gastric cancer. Methods: All cases analyzed were from Surveillance, Epidemiology, and End Results database. The data of the patients with early gastric cancer from 2004 to 2010 was retrospectively analyzed. Patients were distributed to cardia cancer group and non-cardia cancer group. Univariate and multivariate analyses were performed to examine differences between groups. The competitive risk model was made to compare the association with cardia cancer and non-cardia cancer about the causes of death. Propensity score matching (PSM) was performed to reduce the bias. Results: We found that cardia cancer was more common in male patients and the White than that in non-cardia cancer at early stage, signet ring cell carcinoma was more common in non-cardia cancer, and the differentiation of non-cardia cancer was worse. Univariate analysis showed that age, marital status, race, tumor location, histology, grade, stage, and operation or not can determine the prognosis. And the prognosis of patients with cardia cancer was worse than that of non-cardia cancer, according to lymph node metastasis and the depth of tumor invasion. Multivariate analysis showed cardia cancer was an independent prognostic factor for poor prognosis. After PSM, cardia cancer still exhibited poor prognosis. Conclusions: At early stage, cardia cancer had a poor prognosis compared with non-cardia cancer. The prevention and treatment of early cardia cancer need to be seriously treated.

There is an urgent need in clinical practice to measure the stress of parenting. The Caregiver Strain Questionnaire (CGSQ) was found to be useful to measure parenting stress, but it has not been validated among the Chinese population.

Preeclampsia is a gestational hypertensive disease; however, preeclampsia remains poorly understood. Bioinformatics analysis was applied to find novel genes involved in the pathogenesis of preeclampsia and identified CLDN1 as one of the most differentially expressed genes when comparing patients with preeclampsia and healthy controls. The results of the qRT-PCR, Western blotting and immunohistochemistry experiments demonstrated that CLDN1 was significantly downregulated in the chorionic villi in samples from patients with preeclampsia. Furthermore, knockdown of CLDN1 in HTR-8/SVneo cells resulted in the inhibition of proliferation and induction of apoptosis, and overexpression of CLDN1 reversed these effects. In addition, RNA-seq assays demonstrated that the gene BIRC3 is potentially downstream of CLDN1 and is involved in the regulation of apoptosis. Knockdown of CLDN1 confirmed that the expression level of BIRC3 was obviously decreased and was associated with a significant increase in cleaved PARP. Interestingly, the apoptotic effect in CLDN1 knockdown cells was rescued after BIRC3 overexpression. Overall, these results indicate that a decrease in CLDN1 inhibits BIRC3 expression and increases cleaved PARP levels thus participating in the pathogenesis of preeclampsia.

To explore the role of plasma miRNAs in exosomes in early postmenopausal women. Small RNA sequencing was implemented to clarify the expression of miRNA in plasma exosomes obtained from 15 postmenopausal women, divided into groups of osteoporosis, osteopenia, and normal bone mass based on bone mineral density. Differentially expressed miRNAs (DEMs) were identified by comparing miRNA expression profiles. Five putative miRNAs, miR-224-3p, miR-25-5p, miR-302a-3p, miR-642a-3p, and miR-766-5p were confirmed by real-time PCR; miRNA target genes were obtained from 4 databases: miRWalk, miRDB, RNA22, and TargetScan. The miRNA-mRNA- Kyoto Encyclopedia of Genes and Genomes (KEGG) networks were analyzed, and the DEMs' potential role was investigated by gene ontology terms and KEGG pathway annotation. The results suggest that characterizing plasma exosomal miRNA profiles of early postmenopausal women by small RNA sequencing could identify novel exo-miRNAs involved in bone remodeling, and miR-642a-3p maybe contribute to the prediction and diagnosis of early postmenopausal osteoporosis.

Excessive production of inflammatory chemokines and reactive oxygen species (ROS) can cause a feedback cycle of inflammation response that has a negative effect on cutaneous wound healing. The use of wound-dressing materials that simultaneously absorb chemokines and scavenge ROS constitutes a novel 'weeding and uprooting' treatment strategy for inflammatory conditions. In the present study, a composite hydrogel comprising an amine-functionalized star-shaped polyethylene glycol (starPEG) and heparin for chemokine sequestration as well as Cu5.4O ultrasmall nanozymes for ROS scavenging (Cu5.4O@Hep-PEG) was developed. The material effectively adsorbs the inflammatory chemokines monocyte chemoattractant protein-1 and interleukin-8, decreasing the migratory activity of macrophages and neutrophils. Furthermore, it scavenges the ROS in wound fluids to mitigate oxidative stress, and the sustained release of Cu5.4O promotes angiogenesis. In acute wounds and impaired-healing wounds (diabetic wounds), Cu5.4O@Hep-PEG hydrogels outperform the standard-of-care product Promogram® in terms of inflammation reduction, increased epidermis regeneration, vascularization, and wound closure.

Sulfoquinovose (6-deoxy-6-sulfoglucose, SQ) is a component of sulfolipids found in the photosynthetic membranes of plants and other photosynthetic organisms, and is one of the most abundant organosulfur compounds in nature. Microbial degradation of SQ, termed sulfoglycolysis, constitutes an important component of the biogeochemical sulfur cycle. Two sulfoglycolysis pathways have been reported, with one resembling the Embden-Meyerhof-Parnas (sulfo-EMP) pathway, and the other resembling the Entner-Doudoroff (sulfo-ED) pathway. Here we report a third sulfoglycolysis pathway in the bacterium Bacillus megaterium DSM 1804, in which sulfosugar cleavage is catalyzed by the transaldolase SqvA, which converts 6-deoxy-6-sulfofructose and glyceraldehyde 3-phosphate into fructose -6-phosphate and (S)-sulfolactaldehyde. Variations of this transaldolase-dependent sulfoglycolysis (sulfo-TAL) pathway are present in diverse bacteria, and add to the diversity of mechanisms for the degradation of this abundant organosulfur compound.

Rationale: In breast cancer, high intratumor DNA methylation heterogeneity can lead to drug-resistant, metastasis and poor prognosis of tumors, which increases the complexity of cancer diagnosis and treatment. However, most studies are limited to average DNA methylation level of individual CpGs and ignore heterogeneous DNA methylation patterns of cell subpopulations within the tumor. Thus, quantifying the variability in DNA methylation pattern in sequencing reads is valuable for understanding intratumor heterogeneity. Methods: We performed Reduced Representation Bisulfite Sequencing and RNA sequencing for tumor core and tumor periphery regions within one breast tumor. By developing a method named "epialleJS" based on Jensen-Shannon divergence, we detected the differential epialleles between tumor core and tumor periphery (CPDEs). We then explored the correlation between intratumor methylation heterogeneity and hypoxic microenvironment in TCGA breast cancer cohort. Results: More than 70% of CPDEs had higher epipolymorphism in tumor core than tumor periphery, and these CPDEs had lower methylation in tumor core. The CPDEs with lower methylation in tumor core may associate with hypoxic tumor microenvironment. Moreover, we identified a signature of five hypoxia-related DNA methylation markers which can predict the prognosis of breast cancer patients, including a CpG site cg15190451 in gene SLC16A5. Furthermore, immunohistochemical analysis confirmed that the expression of SLC16A5 was associated with clinicopathological characteristics and survival of breast cancer patients. Conclusions: The analysis of intratumor DNA methylation heterogeneity based on epialleles reveals that disordered methylation patterns in tumor core are associated with hypoxic microenvironment, which provides a framework for understanding biological heterogeneous behavior and guidance for developing effective treatment schemes for breast cancer patients.

The INO80 complex, a SWI/SNF family chromatin remodeler, has regulatory effects on ESC self-renewal, somatic cell reprogramming and blastocyst development. However, the role of INO80 in regulating trophoblast cells and recurrent miscarriage (RM) remains elusive. To investigate the in vivo effects of Ino80 in embryo development, we disrupted Ino80 in C57 mice, which resulted in embryonic lethality. Silencing of Ino80 led to decreased survival capacity, migration and invasion of trophoblasts. Furthermore, RNA high-throughput sequencing (RNA-seq) revealed that Ino80 silencing closely resembled the gene expression changes in RM tissues. To investigate the mechanisms for these results, RNA-seq combined with high-throughput sequencing (ChIP-seq) was used in trophoblast cells, and it showed that Ino80 physically occupies promoter regions to affect the expression of invasion-associated genes. Last, Western blotting analyses and immunofluorescence staining revealed that the content of INO80 was reduced in RM patients compared to in healthy controls. This study indicates that INO80 has a specific regulatory effect on the viability, migration and invasion of trophoblast cells. Combined with its regulation of the expression of invasion-associated genes, it has been proposed that epigenetic regulation plays an important role in the occurrence of RM, potentially informing RM therapeutic strategies.