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TcpC is a virulence factor of uropathogenic E. coli (UPEC). It was found that TIR domain of TcpC impedes TLR signaling by direct association with MyD88. It has been a long-standing question whether bacterial pathogens have evolved a mechanism to manipulate MyD88 degradation by ubiquitin-proteasome pathway. Here, we show that TcpC is a MyD88-targeted E3 ubiquitin ligase. Kidney macrophages from mice with pyelonephritis induced by TcpC-secreting UPEC showed significantly decreased MyD88 protein levels. Recombinant TcpC (rTcpC) dose-dependently inhibited protein but not mRNA levels of MyD88 in macrophages. Moreover, rTcpC significantly promoted MyD88 ubiquitination and accumulation in proteasomes in macrophages. Cys12 and Trp106 in TcpC are crucial amino acids in maintaining its E3 activity. Therefore, TcpC blocks TLR signaling pathway by degradation of MyD88 through ubiquitin-proteasome system. Our findings provide not only a novel biochemical mechanism underlying TcpC-medicated immune evasion, but also the first example that bacterial pathogens inhibit MyD88-mediated signaling pathway by virulence factors that function as E3 ubiquitin ligase., Author summary Toll/interleukin-1 receptor domain-containing protein encoded by E. coli (TcpC) is an important virulence factor in many strains of uropathogenic E. coli (UPEC). TcpC-mediated evasion of innate immunity plays an important role in the pathogenesis of UPEC caused urinary tract infection (UTI) including pyelonephritis. In the present study, we show TcpC is an E3 ubiquitin ligase that promotes ubiquitination and degradation of MyD88, hereby blocking the TLR signaling pathway. Our findings not only illuminate the novel biochemical mechanisms underlying TcpC-mediated evasion of innate immunity, but also provide the first example that bacterial pathogens can subvert TLR signaling pathway through virulence factors that function as MyD88-targeted E3 ubiquitin ligase.

Background Use of statins is associated with a reduced risk of hepatocellular carcinoma (HCC). However, the effect of statin use on HCC recurrence is unclear. This study aimed to evaluate the effect of statin use on recurrence after curative resection among patients with HCC. Methods We retrospectively assessed 820 patients with Barcelona Clinic Liver Cancer (BCLC) stage 0 or A HCC who underwent primary resection between January 2001 and June 2016 at Kaohsiung Chang Gung Memorial Hospital. Exposure to statins was defined as use of a statin for at least 3 months before HCC recurrence. Factors that influenced overall survival (OS) and recurrence-free survival (RFS) were analyzed using Cox proportional hazards models. Results Of the 820 patients, 46 (5.6%) used statins (statin group) and 774 (94.4%) did not (non-statin group). During the mean follow-up of 76.5 months, 440 (53.7%) patients experienced recurrence and 146 (17.8%) patients died. The cumulative incidence of HCC recurrence was significantly lower in the statin group than the non-statin group (p = 0.001); OS was not significantly different between groups. In multivariate analysis, age (hazard ratio [HR]: 1.291; p = 0.010), liver cirrhosis (HR: 1.743; p p = 0.001), number of tumors (HR: 1.750; p p = 0.004) and vascular invasion (HR: 1.659; p p p Conclusion Statins may exert a chemo-preventive effect on HCC recurrence after curative resection.

Chromatin dynamics regulated by epigenetic modification is crucial in genome stability and gene expression. Various epigenetic mechanisms have been identified in the pathogenesis of human diseases. Here, we examined the effects of ten epigenetic agents on pseudorabies virus (PRV) infection by using GFP-reporter assays. Inhibitors of bromodomain protein 4 (BRD4), which receives much more attention in cancer than viral infection, was found to exhibit substantial anti-viral activity against PRV as well as a range of DNA and RNA viruses. We further demonstrated that BRD4 inhibition boosted a robust innate immune response. BRD4 inhibition also de-compacted chromatin structure and induced the DNA damage response, thereby triggering the activation of cGAS-mediated innate immunity and increasing host resistance to viral infection both in vitro and in vivo. Mechanistically, the inhibitory effect of BRD4 inhibition on viral infection was mainly attributed to the attenuation of viral attachment. Our findings reveal a unique mechanism through which BRD4 inhibition restrains viral infection and points to its potent therapeutic value for viral infectious diseases., Author summary BRD4 has been well investigated in tumorigenesis for its contribution to chromatin remodeling and gene transcription. BRD4 inhibitors are used as promising chemotherapeutic drugs for cancer therapy. Here, we show a unique mechanism through which BRD4 inhibition broadly inhibits attachment of DNA and RNA viruses through DNA damage-dependent antiviral innate immune activation via the cGAS-STING pathway, in both cell culture and an animal model. STING-associated innate immune signaling has been considered to be a new possibility for cancer therapy, and STING agonists have been tested in early clinical trials. Our data identify BRD4 inhibitors as a potent therapy not only for viral infection but also for cancer immunotherapy.

PurposeTo evaluate the rate of discordance of epidermal growth factor receptor (EGFR) mutation between primary lung tumor and paired distant metastases in non-small-cell lung cancer (NSCLC).MethodsWe performed a meta-analysis of 17 studies (518 cases) assessing discordance rates of EGFR mutation in primary tumors and paired distant metastases. We performed subgroup analyses based on EGFR mutation status in primary tumor (mutant or wildtype), site of distant metastasis (bone, central nervous system (CNS) or lung/ pleural), methods of testing (direct sequencing or allele-specific testing) and timing of metastasis (synchronous or metachronous).ResultsThe overall discordance rate in EGFR mutation was low at 10.36% (95% CI = 4.23% to 18.79%) and varied widely between studies (I2 = 83.18%). The EGFR discordance rate was statistically significantly higher in bone metastases (45.49%, 95% CI = 14.13 to 79.02) than CNS (17.26%, 95% CI = 7.64 to 29.74; P = 0.002) and lung/ pleural metastases (8.17%, 95% CI = 3.35 to 14.85; P < 0.001). Subgroup analyses did not demonstrate any significant effect modification on the discordance rates by the EGFR mutation status in primary lung tumor, methods of testing and timing of metastasis.ConclusionThe overall discordance rate in EGFR mutation between primary lung tumor and paired distant metastases in NSCLC is low, although higher discordance rates were observed in bone metastases compared with CNS and lung/pleural metastases. Future studies assessing the impact of EGFR mutation discordance on treatment outcomes are required.

Colorectal cancer (CRC) is a common and highly lethal form of cancer. Although the etiologic role of Fusobacterium nucleatum (F. nucleatum) in the development of CRC has been elucidated, the specific tumor molecules involved in the progression of CRC induced by F. nucleatum have not been identified. This study investigated several miRNAs and genes involved in the progression of F. nucleatum-induced CRC by Affymetrix miRNA microarray technology and GeneChip Human Transcriptome Array 2.0. The results suggest that miR-4474 and miR-4717 are up-regulated in CRC tissues in response to F. nucleatum infection, compared with the control group (paracancerous tissues), while other genes associated with signaling pathways in cancer, including CREB-binding protein (CREBBP), STAT1, PRKACB, CAMK2B, JUN, TP53 and EWSR1, were dysregulated. Bioinformatic analysis identified CREBBP as the primary aberrantly expressed gene in F. nucleatum-induced CRC. Consistent with the microarray analysis results, real-time RT-PCR analysis demonstrated that the expression of miR-4474/4717 was upregulated while that of CREBBP mRNA was downregulated in CRC patients infected with F. nucleatum. Additionally, CREBBP was identified as a novel target of miR-4474/4717. The results of this study suggest that miR-4474 and miR-4717 are involved in the progression of F. nucleatum-induced CRC by posttranscriptionally regulating the target gene CREBBP.

One of the goals of bone tissue engineering is to mimic native ECM in architecture and function, creating scaffolds with excellent biocompatibility, osteoinductive ability and mechanical properties. The aim of this study was to fabricate nanofibrous matrices by electrospinning a blend of poly (L-lactic-co-glycolic acid) (PLGA), hydroxyapatite (HA), and grapheme oxide (GO) as a favourable platform for bone tissue engineering. The morphology, biocompatibility, mechanical properties, and biological activity of all nanofibrous matrices were compared. The data indicate that the hydrophilicity and protein adsorption rate of the fabricated matrices were significantly increased by blending with a small amount of HA and GO. Furthermore, GO significantly boosted the tensile strength of the nanofibrous matrices, and the PLGA/GO/HA nanofibrous matrices can serve as mechanically stable scaffolds for cell growth. For further test in vitro, MC3T3-E1 cells were cultured on the PLGA/HA/GO nanofbrous matrices to observe various cellular activities and cell mineralization. The results indicated that the PLGA/GO/HA nanofibrous matrices significantly enhanced adhesion, and proliferation in MCET3-E1 cells and functionally promoted alkaline phosphatase (ALP) activity, the osteogenesis-related gene expression and mineral deposition. Therefore, the PLGA/HA/GO composite nanofibres are excellent and versatile scaffolds for applications in bone tissue regeneration.

Understanding the implications of genome-wide association studies (GWAS) for disease biology requires both identification of causal variants and definition of how these variants alter gene function. The non-coding triallelic dinucleotide polymorphism CCR6DNP is associated with risk for rheumatoid arthritis, and is considered likely causal because allelic variation correlates with expression of the chemokine receptor CCR6. Using transcription activator-like effector nuclease (TALEN) gene editing, we confirmed that CCR6DNP regulates CCR6. To identify the associated transcription factor, we applied a novel assay, Flanking Restriction Enhanced Pulldown (FREP), to identify specific association of poly (ADP-ribose) polymerase 1 (PARP-1) with CCR6DNP consistent with the established allelic risk hierarchy. Correspondingly, manipulation of PARP-1 expression or activity impaired CCR6 expression in several lineages. These findings show that CCR6DNP is a causal variant through which PARP-1 regulates CCR6, and introduce a highly efficient approach to interrogate non-coding genetic polymorphisms associated with human disease., Author Summary Genome-wide association studies (GWAS) identify loci associated with human disease risk, but bridging the gap between locus and mechanism has proven particularly difficult in cases where associated variants do not alter coding. We aimed to develop a generalizable approach to this problem. Previously, a dual nucleotide polymorphism within the first intron of CCR6 (termed the CCR6DNP) had been associated with risk for rheumatoid arthritis, but the pathway by which this variant altered gene expression could not be determined. Here, we employed sequence perturbation to confirm a regulatory role for the CCR6DNP. Next, using a new technique termed Flanking Restriction Enhanced Pulldown (FREP), we identified PARP-1 as the protein that regulates CCR6 expression through allelic association with the CCR6DNP, a finding confirmed by chromatin immunoprecipitation and functional assays. These findings reveal an unexpected regulatory pathway for CCR6 implicated in rheumatoid arthritis and other disease by human genetics, and more generally introduce a novel approach to identifying regulatory protein-DNA interactions.

Elevated serum interleukin-6 (IL-6) levels correlates with tumor grade and poor prognosis in cancer patients. IL-6 has been shown to promote tumor lymphangiogenesis through vascular endothelial growth factor-C (VEGF-C) induction in tumor cells. We recently showed that IL-6 also induced VEGF-C expression in lymphatic endothelial cells (LECs). However, the signaling mechanisms involved in IL-6-induces VEGF-C induction in LECs remain incompletely understood. In this study, we explored the causal role of focal adhesion kinase (FAK) in inducing VEGF-C expression in IL-6-stimulated murine LECs (SV-LECs). FAK signaling blockade by NSC 667249 (a FAK inhibitor) attenuated IL-6-induced VEGF-C expression and VEGF-C promoter-luciferase activities. IL-6’s enhancing effects of increasing FAK, ERK1/2, p38MAPK, C/EBPβ, p65 and STAT3 phosphorylation as well as C/EBPβ-, κB- and STAT3-luciferase activities were reduced in the presence of NSC 667249. STAT3 knockdown by STAT3 siRNA abrogated IL-6’s actions in elevating VEGF-C mRNA and protein levels. Moreover, Src-FAK signaling blockade reduced IL-6’s enhancing effects of increasing STAT3 binding to the VEGF-C promoter region, cell migration and endothelial tube formation of SV-LECs. Together these results suggest that IL-6 increases VEGF-C induction and lymphangiogenesis may involve, at least in part, Src-FAK-STAT3 cascade in LECs.

BACKGROUND The purpose of this study was to identify gene polymorphisms of mammary serine protease inhibitor (Maspin) specific to patients with oral cancer susceptibility and clinicopathological status. METHODOLOGY/PRINCIPAL FINDINGS Three single-nucleotide polymorphisms (SNPs) of the Maspin gene from 741 patients with oral cancer and 601 non-cancer controls were analyzed by real-time PCR. The participants with G/G homozygotes or with G/C heterozygotes of Maspin rs2289520 polymorphism had a 2.07-fold (p = 0.01) and a 2.01-fold (p = 0.02) risk of developing oral cancer compared to those with C/C homozygotes. Moreover, gene-gene interaction increased the risk of oral cancer susceptibility among subjects expose to oral cancer related risk factors, including areca, alcohol, and tobacco consumption. CONCLUSION G allele of Maspin rs2289520 polymorphism may be a factor that increases the susceptibility to oral cancer. The interactions of gene to oral cancer-related environmental risk factors have a synergetic effect that can further enhance oral cancer development.

Background Microbial diversity and community structures in acidic hot springs have been characterized by 16S rRNA gene-based diversity surveys. However, our understanding regarding the interactions among microbes, or between microbes and environmental factors, remains limited. Results In the present study, a metagenomic approach, followed by bioinformatics analyses, were used to predict interactions within the microbial ecosystem in Shi-Huang-Ping (SHP), an acidic hot spring in northern Taiwan. Characterizing environmental parameters and potential metabolic pathways highlighted the importance of carbon assimilatory pathways. Four distinct carbon assimilatory pathways were identified in five dominant genera of bacteria. Of those dominant carbon fixers, Hydrogenobaculum bacteria outcompeted other carbon assimilators and dominated the SHP, presumably due to their ability to metabolize hydrogen and to withstand an anaerobic environment with fluctuating temperatures. Furthermore, most dominant microbes were capable of metabolizing inorganic sulfur-related compounds (abundant in SHP). However, Acidithiobacillus ferrooxidans was the only species among key rare microbes with the capability to fix nitrogen, suggesting a key role in nitrogen cycling. In addition to potential metabolic interactions, based on the 16S rRNAs gene sequence of Nanoarchaeum-related and its potential host Ignicoccus-related archaea, as well as sequences of viruses and CRISPR arrays, we inferred that there were complex microbe-microbe interactions. Conclusions Our study provided evidence that there were numerous microbe-microbe and microbe-environment interactions within the microbial community in an acidic hot spring. We proposed that Hydrogenobaculum bacteria were the dominant microbial genus, as they were able to metabolize hydrogen, assimilate carbon and live in an anaerobic environment with fluctuating temperatures. Electronic supplementary material The online version of this article (doi:10.1186/s12864-015-2230-9) contains supplementary material, which is available to authorized users.

Phylogenetic reconstruction is fundamental to study evolutionary biology and historical biogeography. However, there was not a molecular phylogeny of gymnosperms represented by extensive sampling at the genus level, and most published phylogenies of this group were constructed based on cytoplasmic DNA markers and/or the multi-copy nuclear ribosomal DNA. In this study, we use LFY and NLY, two single-copy nuclear genes that originated from an ancient gene duplication in the ancestor of seed plants, to reconstruct the phylogeny and estimate divergence times of gymnosperms based on a complete sampling of extant genera. The results indicate that the combined LFY and NLY coding sequences can resolve interfamilial relationships of gymnosperms and intergeneric relationships of most families. Moreover, the addition of intron sequences can improve the resolution in Podocarpaceae but not in cycads, although divergence times of the cycad genera are similar to or longer than those of the Podocarpaceae genera. Our study strongly supports cycads as the basal-most lineage of gymnosperms rather than sister to Ginkgoaceae, and a sister relationship between Podocarpaceae and Araucariaceae and between Cephalotaxaceae-Taxaceae and Cupressaceae. In addition, intergeneric relationships of some families that were controversial, and the relationships between Taxaceae and Cephalotaxaceae and between conifers and Gnetales are discussed based on the nuclear gene evidence. The molecular dating analysis suggests that drastic extinctions occurred in the early evolution of gymnosperms, and extant coniferous genera in the Northern Hemisphere are older than those in the Southern Hemisphere on average. This study provides an evolutionary framework for future studies on gymnosperms.

Background Acetylcholinesterase (AChE) mainly functions as an efficient terminator for acetylcholine signaling transmission. Here, we reported the effect of AChE on gastric cancer therapy. Methods The expression of AChE in gastric cancerous tissues and adjacent non-cancerous tissues was examined by immunohistochemistry. Gastric cancer cells were treated with AChE delivered by replication-deficient adenoviral vector (Ad.AChE) or oncolytic adenoviral vector (ZD55-AChE), respectively, followed by measurement of cell viability and apoptosis by MTT assay and apoptosis detection assays. In vivo, the tumor growth of gastric cancer xenografts in mice treated with Ad.AChE or ZD55-AChE (1 × 109 PFU) were measured. In addition, the cell viability of gastric cancer stem cells treated with Ad.AChE or ZD55-AChE were evaluated by MTT assay. Results A positive correlation was found between higher level of AChE expression in gastric cancer patient samples and longer survival time of the patients. Ad.AChE and ZD55-AChE inhibited gastric cancer cell growth, and low dose of ZD55-AChE induced mitochondrial pathway of apoptosis in cells. ZD55-AChE repressed tumor growth in vivo, and the anti-tumor efficacy is greater than Ad.AChE. Moreover, ZD55-AChE suppressed the growth of gastric cancer stem cells. Conclusion ZD55-AChE represented potential therapeutic effect for human gastric cancer. Electronic supplementary material The online version of this article (doi:10.1186/1471-2407-14-668) contains supplementary material, which is available to authorized users.

BACKGROUND: Genetic polymorphism is suggested to be associated with human physical performance. The angiotensin I-converting enzyme insertion/deletion (ACE I/D) polymorphism and the α-actinin-3 gene (ACTN3) R577X polymorphism have been most widely studied for such association analysis. However, the findings are frequently heterogeneous. We aim to summarize the associations of ACE I/D and ACTN3 R577X with sport performance by means of meta-analysis. METHODS: We systematically reviewed and quantitatively summarized published studies, until October 31, 2012, on relationship between ACE/ACTN3 genetic polymorphisms and sports performance, respectively. RESULTS: A total of 366 articles on ACE and 88 articles on ACTN3 were achieved by literature search. A significant association was found for ACE II genotype compared to D allele carriage (DD+ID) with increased possibility of physical performance (OR, 1.23; 95% CI, 1.05-1.45). With respect to sport discipline, the II genotype was found to be associated with performance in endurance athletes (OR, 1.35; 95% CI, 1.17-1.55). On the other hand, no significant association was observed for ACTN3 RR genotype as compared to X allele carriage (XX+RX) (OR, 1.03; 95% CI, 0.92-1.15). However, when restricted the analyses to power events, a significant association was observed (OR, 1.21; 95% CI, 1.03-1.42). CONCLUSION: Our results provide more solid evidence for the associations between ACE II genotype and endurance events and between ACTN3 R allele and power events. The findings suggest that the genetic profiles might influence human physical performance.

Despite major advances in next-generation sequencing, assembly of sequencing data, especially data from novel microorganisms or re-emerging pathogens, remains constrained by the lack of suitable reference sequences. De novo assembly is the best approach to achieve an accurate finished sequence, but multiple sequencing platforms or paired-end libraries are often required to achieve full genome coverage. In this study, we demonstrated a method to assemble complete bacterial genome sequences by integrating shotgun Roche 454 pyrosequencing with optical whole genome mapping (WGM). The whole genome restriction map (WGRM) was used as the reference to scaffold de novo assembled sequence contigs through a stepwise process. Large de novo contigs were placed in the correct order and orientation through alignment to the WGRM. De novo contigs that were not aligned to WGRM were merged into scaffolds using contig branching structure information. These extended scaffolds were then aligned to the WGRM to identify the overlaps to be eliminated and the gaps and mismatches to be resolved with unused contigs. The process was repeated until a sequence with full coverage and alignment with the whole genome map was achieved. Using this method we were able to achieved 100% WGRM coverage without a paired-end library. We assembled complete sequences for three distinct genetic components of a clinical isolate of Providencia stuartii: a bacterial chromosome, a novel bla NDM-1 plasmid, and a novel bacteriophage, without separately purifying them to homogeneity.

International audience; The whole-genome duplication (WGD) may provide a basis for the emergence of the very characteristic life style of Saccharomyces cerevisiae-its fermentation-oriented physiology and its capacity of growing in anaerobiosis. Indeed, we found an over-representation of oxygen-responding genes in the ohnologs of S. cerevisiae. Many of these duplicated genes are present as aerobic/hypoxic(anaerobic) pairs and form a specialized system responding to changing oxygen availability. HYP2/ANB1 and COX5A/COX5B are such gene pairs, and their unique orthologs in the 'non-WGD' Kluyveromyces lactis genome behaved like the aerobic versions of S. cerevisiae. ROX1 encodes a major oxygen-responding regulator in S. cerevisiae. The synteny, structural features and molecular function of putative KlROX1 were shown to be different from that of ROX1. The transition from the K. lactis-type ROX1 to the S. cerevisiae-type ROX1 could link up with the development of anaerobes in the yeast evolution. Bioinformatics and stochastic analyses of the Rox1p-binding site (YYYATTGTTCTC) in the upstream sequences of the S. cerevisiae Rox1p-mediated genes and of the K. lactis orthologs also indicated that K. lactis lacks the specific gene system responding to oxygen limiting environment, which is present in the 'post-WGD' genome of S. cerevisiae. These data suggested that the oxygen-responding system was born for the specialized physiology of S. cerevisiae.

RNA interference (RNAi) is the process of mRNA degradation induced by double-stranded RNA in a sequence-specific manner. Different types of promoters, such as U6, H1, tRNA, and CMV, have been used to control the inhibitory effect of RNAi expression vectors. In the present study, we constructed two shRNA expression vectors, respectively, controlled bytRNAlysand CMV enhancer-tRNAlyspromoters. Compared to the vectors withtRNAlysor U6 promoter, the vector with a CMV enhancer-tRNAlyspromoter silenced pokemon more efficiently on both the mRNA and the protein levels. Meanwhile, the silencing of pokemon inhibited the proliferation of MCF7 cells, but the induction of apoptosis of MCF7 cells was not observed. We conclude that the CMV enhancer-tRNAlyspromoter may be a powerful tool in driving intracellular expression of shRNA which can efficiently silence targeted gene.

Fatty acid desaturases are enzymes that introduce double bonds into the hydrocarbon chains of fatty acids. The fatty acid desaturases from 37 cyanobacterial genomes were identified and classified based upon their conserved histidine-rich motifs and phylogenetic analysis, which help to determine the amounts and distributions of desaturases in cyanobacterial species. The filamentous orN2-fixing cyanobacteria usually possess more types of fatty acid desaturases than that of unicellular species. The pathway of acyl-lipid desaturation for unicellular marine cyanobacteriaSynechococcusandProchlorococcusdiffers from that of other cyanobacteria, indicating different phylogenetic histories of the two genera from other cyanobacteria isolated from freshwater, soil, or symbiont. StrainGloeobacter violaceusPCC 7421 was isolated from calcareous rock and lacks thylakoid membranes. The types and amounts of desaturases of this strain are distinct to those of other cyanobacteria, reflecting the earliest divergence of it from the cyanobacterial line. Three thermophilic unicellular strains,Thermosynechococcus elongatusBP-1 and twoSynechococcusYellowstone species, lack highly unsaturated fatty acids in lipids and contain only oneΔ9desaturase in contrast with mesophilic strains, which is probably due to their thermic habitats. Thus, the amounts and types of fatty acid desaturases are various among different cyanobacterial species, which may result from the adaption to environments in evolution.

Background Serine/threonine kinases (STKs) have been found in an increasing number of prokaryotes, showing important roles in signal transduction that supplement the well known role of two-component system. Cyanobacteria are photoautotrophic prokaryotes able to grow in a wide range of ecological environments, and their signal transduction systems are important in adaptation to the environment. Sequence information from several cyanobacterial genomes offers a unique opportunity to conduct a comprehensive comparative analysis of this kinase family. In this study, we extracted information regarding Ser/Thr kinases from 21 species of sequenced cyanobacteria and investigated their diversity, conservation, domain structure, and evolution. Results 286 putative STK homologues were identified. STKs are absent in four Prochlorococcus strains and one marine Synechococcus strain and abundant in filamentous nitrogen-fixing cyanobacteria. Motifs and invariant amino acids typical in eukaryotic STKs were conserved well in these proteins, and six more cyanobacteria- or bacteria-specific conserved residues were found. These STK proteins were classified into three major families according to their domain structures. Fourteen types and a total of 131 additional domains were identified, some of which are reported to participate in the recognition of signals or substrates. Cyanobacterial STKs show rather complicated phylogenetic relationships that correspond poorly with phylogenies based on 16S rRNA and those based on additional domains. Conclusion The number of STK genes in different cyanobacteria is the result of the genome size, ecophysiology, and physiological properties of the organism. Similar conserved motifs and amino acids indicate that cyanobacterial STKs make use of a similar catalytic mechanism as eukaryotic STKs. Gene gain-and-loss is significant during STK evolution, along with domain shuffling and insertion. This study has established an overall framework of sequence-structure-function interactions for the STK gene family, which may facilitate further studies of the role of STKs in various organisms.

Background Infectious agents have been shown to contribute to the development of lymphoid malignancies. The different distribution of lymphoid malignancies in Asian and Western populations suggests possibly different etiologies in Asian populations. Herpes zoster infection, commonly seen in immunocompromised persons, has been reported to be associated with lymphoid malignancies in retrospective case–control studies from Western populations, but the results are controversial and large-scale prospective studies from Asian populations are lacking. Methods A nationwide population-based matched-controlled prospective study on Taiwanese patients was performed using the National Health Insurance Research Database from 1996 to 2007. Herpes zoster and malignancies were defined by compatible ICD-9-CM (International Classification of Disease, 9th Revision, Clinical Modification) codes. Patients who had been diagnosed with any malignancies before herpes zoster, with known viral infections including human immunodeficiency virus, and duration from herpes zoster to diagnosis of malignancies less than 6 months were excluded. Results Of 42,498 patients with herpes zoster prior to the diagnosis of any malignancies, the cumulative incidence for lymphoid malignancies was 0.11% (n = 48), compared with 0.06% (n = 106) in 169,983 age- and gender-matched controls (univariate hazard ratio (HR): 1.82, 95%CI: 1.29-2.55). The most common lymphoid malignancy was non-Hodgkin’s lymphoma (60.4%, n = 29), followed by multiple myeloma (27.1%, n = 13). Risk for developing lymphoid malignancies is significantly higher in herpes zoster patients (log rank P = 0.005). After adjusting for presence of any comorbidities in Charlson comorbidity index, time-dependent covariate for herpes group, and income category using Cox proportional hazard regressions, herpes zoster patients had an increased risk of developing lymphoid malignancies (adjusted HR: 1.68, 95%CI: 1.35-2.42, P = 0.0026), but did not have an increased risk of developing non-lymphoid malignancies (adjusted HR: 1.00, 95%CI: 0.91-1.05, P = 0.872). Conclusion Preceding herpes zoster infection is an independent risk marker for subsequent lymphoid malignancies in Taiwanese subjects. Further studies are warranted for pathogenesis exploration and preventive strategies in Asian populations.

Background This study aimed to analyze the pattern of lymphogenous and hematogenous metastases in patients with stage IVb thymic carcinomas and identify prognostic factors for their survivals. Methods Between September 1978 and October 2014, 68 patients with pathologically confirmed stage IVb thymic carcinomas were treated at Fudan University Shanghai Cancer Center. Forty-three patients had lymph node involvement without distant metastases, and the remaining 25 patients had hematogenous metastases. Clinical-pathological characteristics, including age, sex, histologic subtype, tumor size, metastasis, treatment modalities, such as surgical resection, radiotherapy, and chemotherapy, and clinical outcomes, such as overall survival (OS) and progression free survival (PFS), were analyzed. Results The median follow-up time was 22 months (range, 1–126 months). The median OS of all patients with stage IVb thymic carcinomas was 30 months, and the 5-year overall survival rate was 25.1%. The median PFS was 11 months, and the 5-year PFS was 17.9%. Stage IVb patients with lymph node involvement had a better survival than those with distant metastasis (40 vs. 20 months, p = 0.002). Patients with myasthenia gravis had a worse prognosis (p = 0.033). Multivariate analysis identified metastatic status as an independent prognostic factor for OS in patients with stage IVb thymic carcinomas. Conclusions Patients with lymph node involvement had a better survival than those with distant metastases. Much work remains to investigate the prognosis of patients with stage IVb thymic carcinomas and to explore different treatment strategies for patients with lymph node involvement and distant metastases.

Background About 80% of patients with GIST would experience tumor recurrence or metastasis after radical resection. The most common site of the metastasis is the liver. Imatinib mesylate has been proved effective for advanced GIST. The present study was designed to further observe the effectiveness of the imatinib mesylate treatment on the recurrent GIST and the correlation between the liver metastasis and the outcome. Methods Forty-two patients who had recurrent GIST after the first radical resection were enrolled. According to the recurrent sites, the patients were divided into 3 groups: group LG (recurrent liver GISTs), group AG (recurrent abdominal GISTs) and group ALG (recurrent abdominal and liver GISTs). All the patients were given imatinib mesylate at an initial dose of 400 mg per day. Their clinical data was prospectively collected. A follow-up over 3 years was conducted. Tumor response, time to progression and survival were evaluated. Results The long-term Imatinib mesylate treatment was safe and well tolerated. At a median follow-up time for 39.5 months, the 3-year survival rate was 66.7%. Median TTP and OS were 37 months (95% CI: 28.2~45.8 months) and 48 months (95% CI: 37.0~58.9 months), respectively. There was no statistical difference in tumor response among the 3 groups. The similar TTP (P = 0.291) and OS (P = 0.160) were observed in the 3 groups. Conclusions The imatinib mesylate treatment could prolong the survival of the patients who have recurrent GIST after the radical surgery in spite of an existence of the liver metastasis. Survival was not significantly affected by liver metastasis when imatinib mesylate was warranted.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder in reproductive-aged women that is comprised of two out of the following three features: hyperandrogenism, oligo- or amenorrhea, or polycystic ovaries. In addition to infertility, many women with PCOS have metabolic dysregulation that increases the risk of developing type 2 diabetes, hypertension, and non-alcoholic fatty liver disease. Changes in the gut microbiome are associated with PCOS and gut microbes may be involved in the pathology of this disorder. Since PCOS often manifests in the early reproductive years, puberty is considered to be a critical time period for the development of PCOS. Exposure to sex steroid hormones during development results in permanent, organizational effects, while activational effects are transient and require the continued presence of the hormone. Androgens exert organizational effects during prenatal or early post-natal development, but it is unclear whether androgen excess results in organizational or activational effects during puberty. We recently developed a letrozole-induced PCOS mouse model that recapitulates both reproductive and metabolic phenotypes of PCOS. In this study, we investigated whether letrozole treatment of pubertal female mice exerts organizational or activational effects on host physiology and the gut microbiome. Two months after letrozole removal, we observed recovery of reproductive and metabolic parameters, as well as diversity and composition of the gut microbiome, indicating that letrozole treatment of female mice during puberty resulted in predominantly activational effects. These results suggest that if exposure to excess androgens during puberty leads to the development of PCOS, reduction of androgen levels during this time may improve reproductive and metabolic phenotypes in women with PCOS. These results also imply that continuous letrozole exposure is required to model PCOS in pubertal female mice since letrozole exerts activational rather than organizational effects during puberty.