RcSPL1-RcTAF15b regulates the flowering time of rose (Rosa chinensis).

Rose (Rosa chinensis), which is an economically valuable floral species worldwide, has three types, namely once-flowering (OF), occasional or re-blooming (OR), and recurrent or continuous flowering (CF). However, the mechanism underlying the effect of the age pathway on the duration of the CF or OF juvenile phase is largely unknown. In this study, we observed that the RcSPL1 transcript levels were substantially upregulated during the floral development period in CF and OF plants. Additionally, accumulation of RcSPL1 protein was controlled by rch-miR156. The ectopic expression of RcSPL1 in Arabidopsis thaliana accelerated the vegetative phase transition and flowering. Furthermore, the transient overexpression of RcSPL1 in rose plants accelerated flowering, whereas silencing of RcSPL1 had the opposite phenotype. Accordingly, the transcription levels of floral meristem identity genes (APETALA1, FRUITFULL, and LEAFY) were significantly affected by the changes in RcSPL1 expression. RcTAF15b protein, which is an autonomous pathway protein, was revealed to interact with RcSPL1. The silencing and overexpression of RcTAF15b in rose plants led to delayed and accelerated flowering, respectively. Collectively, the study findings imply that RcSPL1-RcTAF15b modulates the flowering time of rose plants.

Enhancer methylation dynamics drive core transcriptional regulatory circuitry in pan-cancer.

Accumulating evidence has demonstrated that enhancer methylation has strong and dynamic regulatory effects on gene expression. Some transcription factors (TFs) can auto- and cross-regulate in a feed-forward manner, and cooperate with their enhancers to form core transcriptional regulatory circuitries (CRCs). However, the elaborated regulatory mechanism between enhancer methylation and CRC remains the tip of the iceberg. Here, we revealed that DNA methylation could drive the tissue-specific enhancer basal transcription and target gene expression in human cancers. By integrating methylome, transcriptome, and 3D genomic data, we identified enhancer methylation triplets (enhancer methylation-enhancer transcription-target gene expression) and dissected potential regulatory patterns within them. Moreover, we observed that cancer-specific core TFs regulated by enhancers were able to shape their enhancer methylation forming the enhancer methylation-driven CRCs (emCRCs). Further parsing of clinical implications showed rewired emCRCs could serve as druggable targets and prognostic risk markers. In summary, the integrative analysis of enhancer methylation regulome would facilitate portraying the cancer epigenomics landscape and developing the epigenetic anti-cancer approaches.

Comprehensive characterization genetic regulation and chromatin landscape of enhancer-associated long non-coding RNAs and their implication in human cancer.

Long non-coding RNAs (lncRNAs) that emanate from enhancer regions (defined as enhancer-associated lncRNAs, or elncRNAs) are emerging as critical regulators in disease progression. However, their biological characteristics and clinical relevance have not been fully portrayed. Here, based on the traditional expression quantitative loci (eQTL) and our optimized residual eQTL method, we comprehensively described the genetic effect on elncRNA expression in more than 300 lymphoblastoid cell lines. Meanwhile, a chromatin atlas of elncRNAs relative to the genetic regulation state was depicted. By applying the maximum likelihood estimate method, we successfully identified causal elncRNAs for protein-coding gene expression reprogramming and showed their associated single nucleotide polymorphisms (SNPs) favor binding of transcription factors. Further epigenome analysis revealed two immune-associated elncRNAs AL662844.4 and LINC01215 possess high levels of H3K27ac and H3K4me1 in human cancer. Besides, pan-cancer analysis of 3D genome, transcriptome, and regulatome data showed they potentially regulate tumor-immune cell interaction through affecting MHC class I genes and CD47, respectively. Moreover, our study showed there exist associations between elncRNA and patient survival. Finally, we made a user-friendly web interface available for exploring the regulatory relationship of SNP-elncRNA-protein-coding gene triplets (http://bio-bigdata.hrbmu.edu.cn/elncVarReg). Our study provides critical mechanistic insights for elncRNA function and illustrates their implications in human cancer.

Characterization of the emerging multidrug-resistant Salmonella enterica serotype Kentucky ST314 in China.

Salmonella enterica serotype Kentucky (S. Kentucky) is an important Salmonella serotype with multiple sequence types (ST) with a worldwide incidence. We identified 8 STs from 180 strains of S. Kentucky, and ST314 emerged as the most commonly encountered ST. Drug susceptibility testing revealed that ST314 had multiple resistance properties, and 75.5% of the strains were resistant to three or more classes of antimicrobials. The rate of resistance to chloramphenicol, florfenicol, sulfafurazole and tetracycline were greater than 60%. The rates of ST314 resistance to quinolones were as follows: ciprofloxacin, 32.1%; nalidixic acid, 16%; and ofloxacin, 7.5%. Investigating the mechanism of quinolone resistance of ST314 revealed that mutations in the quinolone resistance-determining regions were rare, and resistance mainly occurred due to the resistance genes carried by plasmids. Only 1.9% (2/106) of ST314 strains had mutations in the quinolone resistance-determining regions (QRDR). The drug resistance genes of ST314 were primarily of plasmid-mediated quinolone resistance (PMQR). The detection rate of Salmonella genomic island 1 (SGI1) in ST314 was 12.3%. XbaI-pulsed-field gel electrophoresis revealed that S. enterica Kentucky ST314 was capable of cross-regional and cross-host transmission in China. We found ST314 to be the dominant S. Kentucky ST in China, and it carried multidrug resistance. This is the first report about the emergence of quinolone-resistant S. enterica Kentucky ST314 in China, which is different from previous reports, and the findings of the present study suggest that the mechanism of quinolone resistance in these strains are plasmid-mediated. Notably, plasmids carrying resistance genes may promote the rapid spread of ciprofloxacin resistance.

Fourth Generation Cephalosporin Resistance Among Salmonella enterica Serovar Enteritidis Isolates in Shanghai, China Conferred by bla CTX-M-55 Harboring Plasmids.

In this study, we investigated the pattern of antimicrobial resistance in Salmonella enterica serotype Enteritidis isolates in Shanghai, China from 2005 to 2014. We found the first isolates with resistance to the fourth-generation cephalosporin cefepime starting in 2010. Furthermore, we analyzed the epidemic characteristics and mechanisms of underlying cefepime resistance in S. Enteritidis isolates found from 2010. In total, 38 of 2,914 (1.30%) isolates were identified as cefepime-resistant S. Enteritidis (CRSE) isolates by Kirby-Bauer disk diffusion. Two isolates were from animal derived food sources; 36 isolates were from fecal samples of human patients with salmonellosis. Antimicrobial susceptibility testing using the agar dilution method revealed that all CRSE isolates showed additional resistances at least to ceftazidime, cefotaxime, and ampicillin. Additionally, pulsed-field gel electrophoresis (PFGE) profiles indicated that 89.47% of CRSE isolates also displayed similar PFGE patterns. Five types of ß-lactamase genes, bla CTX-M (100.00%, 38/38), bla SHV (65.79%, 25/38), bla TEM (52.63%, 20/38), bla ACC (18.42%, 7/38), and bla PSE (5.26%, 2/38) were detected by PCR and sequencing. Among bla CTX-M genes, bla CTX-M-55 was the dominant type (84.21%, 32/38). Conjugation and transformation experiments along with plasmid replicon typing revealed that bla CTX-M-55 was located on plasmids of various replicon types with sizes ranging from 76.8 to 138.9 kb. Plasmid sequence analysis also showed that the bla CTX-M-55 gene was mobilized mainly by the ISEcp1-bla CTX-M-55-ORF477 transposition unit and had its own ISEcp1-based promoter, which accelerated the expression and transmission of bla CTX-M-55. Analysis of whole genome sequences (Illumina) of one selected transformant SH12G706-C showed high similarity of the bla CTX-M-55 carrying plasmid with the IncI1 plasmid backbone p628-CTX-M of Klebsiella pneumoniae detected in 2010 in China. The present study demonstrated that the bla CTX-M-55 gene mobilized by ISEcp1- bla CTX-M-55-ORF477 was the main feature shared by CRSE isolates and seems to play an important role for transmission of cefepime resistance. The number of CRSE isolates is rising annually, and the strong dissemination ability of ISEcp1-bla CTX-M-55-ORF477-harboring plasmids among different species represents an important threat to the therapeutic effectiveness of cefepime.

Ciprofloxacin-Resistant Salmonella enterica Serovar Kentucky ST198 in Broiler Chicken Supply Chain and Patients, China, 2010-2016.

Salmonella enterica serovar Kentucky (S. Kentucky) sequence type 198 has emerged as a global zoonotic pathogen. We explored Salmonella enterica serovar Kentucky ST198 samples from the broiler chicken supply chain and patients between 2010 and 2016. Here, we collected 180 S. Kentucky isolates from clinical cases and the poultry supply chain. We performed XbaI pulsed-field gel electrophoresis and multilocus sequence typing. We assessed mutations in the quinolone resistance-determining regions and screened for the presence of the Salmonella genomic island 1 (SGI1). We determined that 63 (35.0%) of the 180 isolates were S. Kentucky ST198. Chinese strains of S. Kentucky ST198 have a high transmission of ciprofloxacin resistance (38/63, 60.3%) and a high risk of multidrug resistance. The quinolone resistance of the S. Kentucky ST198 strain found in China may be due to mutations in its quinolone resistance-determining region. Our study firstly revealed that ciprofloxacin-resistant S. Kentucky ST198 strains can undergo cross-host transmission, thereby causing a serious foodborne public health problem in China.

Molecular epidemiology and antimicrobial resistance of invasive non-typhoidal Salmonella in China, 2007-2016.

PURPOSE: Human infections caused by invasive non-typhoidal Salmonella (iNTS) are highly prevalent worldwide. However, data for such infections in China are scarce. This study reports the epidemiology of iNTS in China. METHODS: INTS isolates were recovered from blood and other clinical specimens collected during 2007-2016 across five provinces (Shanghai, Xinjiang, Fujian, Guangxi, and Chongqing) in China. Antimicrobial susceptibility was performed using the agar dilution method and molecular epidemiology was performed using standard microbiological techniques. RESULTS: A total of 178 iNTS isolates were recovered from approximately 9700 patient specimens during 2007-2016. The predominant serovars were Salmonella Enteritidis (57/178, 32%), Salmonella Choleraesuis (47/178, 26.4%), and Salmonella Typhimurium (24/178, 13.5%). Up to 50 isolates (28.1%) were from patients who were ≤1 year of age, while 28 (15.7%) were from patients who were ≥60 years. Among these isolates, high rates of resistance to nalidixic acid (114/178, 64%), sulfisoxazole (59%), ciprofloxacin (15.2%), and cefotaxime (8.4%) were found. Moreover, 53.4% (95/178) exhibited multidrug resistance, and 3.9% (7/178) showed co-resistance to third-generation cephalosporins and ciprofloxacin. Steadily increasing numbers of nalidixic acid, cefotaxime, and ciprofloxacin-resistant isolates, but decreasing numbers of multidrug resistance isolates were detected during the study period. Detection of quinolone genes in 114 nalidixic acid-resistant isolates showed that 58.3% (67/114) harbored plasmid-mediated quinolone resistance (PMQR) genes [aac(6´)-Ib-cr, qnrA, qnrB, oqxAB, qepA, qnrS, and qnrD] and 98.2% (112/114) exhibited mutations in quinolone resistance determining regions [gyrA, parC, and parE]. Furthermore, we detected beta-lactamases genes in the ceftriaxone-resistant isolates. The most common were blaTEM-1 (93.3%), followed by blaCTX-M-55 (40%), blaCMY-2 (33.3%), and blaOXA-1 (33.3%). Finally, a range of pulsed-field gel electrophoresis patterns were detected among the Salmonella Enteritidis and Salmonella Typhimurium isolates. CONCLUSION: High rates of multidrug resistance and steadily increasing cefotaxime and ciprofloxacin-resistant iNTS could pose a significant challenge for the effective treatment of salmonellosis in China.

Identifying subpathway signatures for individualized anticancer drug response by integrating multi-omics data.

BACKGROUND: Individualized drug response prediction is vital for achieving personalized treatment of cancer and moving precision medicine forward. Large-scale multi-omics profiles provide unprecedented opportunities for precision cancer therapy. METHODS: In this study, we propose a pipeline to identify subpathway signatures for anticancer drug response of individuals by integrating the comprehensive contributions of multiple genetic and epigenetic (gene expression, copy number variation and DNA methylation) alterations. RESULTS: Totally, 46 subpathway signatures associated with individual responses to different anticancer drugs were identified based on five cancer-drug response datasets. We have validated the reliability of subpathway signatures in two independent datasets. Furthermore, we also demonstrated these multi-omics subpathway signatures could significantly improve the performance of anticancer drug response prediction. In-depth analysis of these 46 subpathway signatures uncovered the essential roles of three omics types and the functional associations underlying different anticancer drug responses. Patient stratification based on subpathway signatures involved in anticancer drug response identified subtypes with different clinical outcomes, implying their potential roles as prognostic biomarkers. In addition, a landscape of subpathways associated with cellular responses to 191 anticancer drugs from CellMiner was provided and the mechanism similarity of drug action was accurately unclosed based on these subpathways. Finally, we constructed a user-friendly web interface-CancerDAP ( http://bio-bigdata.hrbmu.edu.cn/CancerDAP/ ) available to explore 2751 subpathways relevant with 191 anticancer drugs response. CONCLUSIONS: Taken together, our study identified and systematically characterized subpathway signatures for individualized anticancer drug response prediction, which may promote the precise treatment of cancer and the study for molecular mechanisms of drug actions.

Highly Prevalent Multidrug-Resistant Salmonella From Chicken and Pork Meat at Retail Markets in Guangdong, China.

This study aimed to investigate the prevalence, serotype distribution, and antibiotic resistance, and to characterize the extended spectrum ß-lactamases (ESBLs) producing Salmonella isolates from chicken and pork meats from retail markets in Guangdong province, China. A total of 903 retail meat samples (475 chicken and 428 pork meats) were obtained from six cities (Guangzhou, Shenzhen, Heyuan, Shaoguan, Foshan, and Yunfu) of Guangdong province between May 2016 and April 2017. High levels of Salmonella contamination were detected in chicken (302/475, 63.6%) and pork (313/428, 73.1%). Thirty-eight serotypes were identified in 615 detected Salmonella, and the serotypes varied greatly between chicken and pork samples. Agona (55/302, 18.2%), Corvallis (45/302, 14.9%), Kentucky (38/302, 12.6%), Mbandaka (32/302, 10.6%) was the dominant serotypes in chicken samples. However, Typhimurium (78/313, 24.9%), Rissen (67/313, 24.1%), Derby (66/313, 21.1%), and London (48, 15.3%) were the most common in pork samples. High rates of antibiotic resistance were found to sulfisoxazole (468/615, 76.1%), tetracycline (463/615, 75.3%), ampicillin (295/615, 48.0%), and ofloxacin (275/615, 44.7%). Notably, antimicrobial susceptibility tests identified resistance to polymyxin B (12/615, 2.0%) and imipenem (3/615, 0.5%). Multidrug-resistance (MDR) was detected in Salmonella isolated from chicken (245/302, 81.1%) and pork (229/313, 73.2%). The resistance rate of different Salmonella serotypes varied widely. Especially, isolates such as Typhimurium, Agona, Corvallis and Kentucky exhibited highly resistance to antibiotics. The MDR rate of Salmonella isolates from chicken was significantly higher than that from pork isolates (P < 0.05). Twenty-one Salmonella isolates were identified as ESBLs-producing, covering six Salmonella serotypes and displaying different pulse field gel electrophoresis (PFGE) genotypes. BlaOXA-1 was the dominant ESBLs gene (9/21, 42.9%), followed by blaCTX-M-55 (5/21, 23.8%). This study indicated that Salmonella was widespread in chicken and pork from retail markets in Guangdong province and the isolates showed high multidrug-resistance, especially the known multidrug-resistant Salmonella serotypes. Therefore, it is important to focus on Salmonella serotypes and strengthen the long-term monitoring of MDR Salmonella serotypes in animal-derived foods.

High-levels of resistance to quinolone and cephalosporin antibiotics in MDR-ACSSuT Salmonella enterica serovar Enteritidis mainly isolated from patients and foods in Shanghai, China.

In this study, 2887 Salmonella strains were mainly obtained from patients and foods in Shanghai from 2006 to 2014 in order to assess the susceptibility to 16 antibiotics. Among them, 3.8% (110/2887) S. Enteritidis isolates were shown to have an ACSSuT (ampicillin, chloramphenicol, streptomycin, sulfamethoxazole, and tetracycline) resistance pattern. The resistance genes of ACSSuT included sul2 (74.55%), flo (67.27%), tetA (49.09%), and aph(3)-IIa (46.36%). In addition, class 1 integron profiles were detected in 9 isolates, and 55.6% (5/9) were shown to carry resistant genes against aminoglycosides and sulfonamides. Moreover, these isolates had a high rate of resistance to nalidixic acid (95.29%), cefotaxime (70.64%), cefepime (58.72%), and ceftazidime (48.62%). Detection of quinolone genes showed that 93.64% (103/110) of the strains had gyrA single mutations (D87G, D87Y, D87N, S83Y, and S83F), where D87G was the dominant mutation in 55.45% isolates. 19.1% (21/110) isolates carried plasmid-mediated quinolone resistance (PMQR) genes (qnrB and aac(6')-Ib-cr), and the most prevalent was qnrB. Furthermore, we also detected ESBLS genes. The most common were blaCTX-M-55 (57.27%) followed by blaTEM (23.6%) and blaOXY (4.55%). Mart, prot6E, steB, fimA, and sopE2 genes (100%) were the most in these isolates. The strains in the dominant PFGE profiles of G1 were all co-resistant to quinolones, cephalosporins, and ACSSuT, and were isolated from different sources. This suggests that existence of these genes lead to the emergence of high-levels of resistance to quinolone and cephalosporin in these ACSSuT resistance pattern isolates. And these isolates are transmitted between humans and food.

Multi-tunable self-assembled morphologies of stimuli-responsive diblock polyampholyte films on solid substrates.

Intelligent polymers, due to their sensitive stimuli response to changes in the environment, have gained increasing amounts of attention over recent years and have become a popular topic in polymer materials science. In this study, the aggregation behaviors and stimuli responses of the stimuli-responsive diblock polyampholyte poly(2-(dimethylamino)ethyl methacrylate)-b-poly(acrylic acid) (PDMAEMA-b-PAA) are conveniently tunable by introducing pH changes, temperature changes, salt addition and surfactant neutralization. Under different pH values, either globular or fractal self-assemblies can be observed in which the latter have crystal properties. Salts and alkalis can promote the fractal aggregation growth because their deposited crystals can act as nucleation sites for the polyampholyte chains. A combination of fluorescence spectroscopy, atom force microscopy and transmission electron microscopy revealed that the presence of anionic surfactants in the PDMAEMA-b-PAA solutions promoted the solubility of the polyampholyte, consequently leading to a more homogeneous distribution of the polymer chains on the solid substrate upon drying the mixtures. The fractal formation was suppressed for the studied Gemini surfactants, and a higher surfactant hydrophobicity results in an earlier start of the formation of the fractal pattern.

Dual-stimuli responsive behaviors of diblock polyampholyte PDMAEMA-b-PAA in aqueous solution.

Two poly(2-(dimethylamino)ethyl methacrylate)-b-poly(acrylic acid) diblock copolymers, PDMAEMA(84)-b-PAA(18) and PDMAEMA(50)-b-PAA(18), were synthesized by the atom transfer radical polymerization (ATRP) and their dual-stimuli responsive behaviors to the changes in temperature and pH in aqueous solutions were investigated by UV-vis spectroscopy, dynamic light scattering (DLS), (1)H NMR spectroscopy and surface tension measurement. Different from PDMAEMA(84)-b-PAA(18) solutions where no aggregation is observed between pH 7.0 and 9.5, the PDMAEMA(50)-b-PAA(18) aggregates can exist in this broad pH range due to the hydrophobic interactions among the charge-balanced polyampholyte chains. At high pH, e.g., 11.0, the DMAEMA segments collapse to form the core of micelles due to the hydrophobic property of the de-protonized DMAEMA stabilized with the highly ionized AA segments on the surface of the micelles upon heating. At pH around the IEP, e.g., 9.5, large micelles can be formed in PDMAEMA(84)-b-PAA(18) solution upon heating, just like that at pH 11.0, while PDMAEMA(50)-b-PAA(18) first formed the micelles due to the electrostatic attraction between ionized AA segments and protonated DMAEMA segments, but the aggregation of the micelles was hardly happened upon heating due to the smaller DMAEMA segment. Moreover, LCST can be exactly estimated by surface tension experiment.