Cyclic dinucleotides are a newly expanded class of second messengers that contribute to the regulation of multiple different pathways in bacterial, eukaryotic, and archaeal cells. The recently identified Vibrio cholerae dinucleotide cyclase (DncV, the gene product of VC0179) can generate three different cyclic dinucleotides and preferentially synthesize a hybrid cyclic-GMP-AMP. Here, we report the crystal structural and functional studies of DncV. We unexpectedly observed a 5-methyltetrahydrofolate diglutamate (5MTHFGLU2) molecule bound in a surface pocket opposite the nucleotide substrate-binding groove of DncV. Subsequent mutagenesis and functional studies showed that the enzymatic activity of DncV is regulated by folate-like molecules, suggesting the existence of a signaling pathway that links folate-like metabolism cofactors to the regulation of cyclic dinucleotide second messenger synthesis. Sequence analysis showed that the residues involved in 5MTHFGLU2 binding are highly conserved in DncV orthologs, implying the presence of this regulation mechanism in a wide variety of bacteria.

The Square Kilometre Array (SKA) will be the world's largest and most sensitive radio telescope. It will address fundamental unanswered questions about our Universe including how the first stars and galaxies formed after the big bang, how dark energy is accelerating the expansion of the Universe, the role of magnetism in the cosmos, the nature of gravity, and the search for life beyond Earth. This project envisages the construction of 133 15-m antennas in South Africa and 131,072 log-periodic antennas in Australia, together with the associated infrastructure in the two desert sites. In addition, the SKA is an exemplar Big Data project, with data rates of over 10 Tbps being transported from the telescope to HPC/HTC facilities.

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PICT-1 was originally identified as a tumor suppressor. Here, we found that PICT-1 overexpression triggered pro-death autophagy without nucleolar disruption or p53 accumulation in U251 and MCF7 cells. Truncated PICT-1 fragments 181-346 and 1-346, which partly or totally lack nucleolar localization, showed weaker autophagy-inducing effects than full-length PICT-1 and a well-defined nucleolar mutant (181-479). Furthermore, PICT-1 partly localizes to the nucleolar fibrillar center (FC) and directly binds to ribosomal DNA (rDNA) gene loci, where it interacts with upstream binding factor (UBF). Overexpression of PICT-1 or the 181-479 mutant, but not the 1-346 or 181-346 mutants, markedly inhibited the phosphorylation of UBF and the recruitment of rRNA polymerase I (Pol I) to the rDNA promoter in response to serum stimulation, thereby suppressing rRNA transcription, suggesting that rRNA transcription inhibition might be an important contributor to PICT-1-induced autophagy. This is supported by the finding that CX-5461, a specific Pol I inhibitor, also induced autophagy. In addition, both CX-5461 and PICT-1, but not the 1-346 or 181-346 mutants, significantly suppressed the activation of the Akt/mTOR/p70S6K signaling pathway. Our data show that PICT-1 triggers pro-death autophagy through inhibition of rRNA transcription and the inactivation of AKT/mTOR/p70S6K pathway, independent of nucleolar disruption and p53 activation.

BackgroundBacterial species belonging to the genus Exiguobacterium are facultative anaerobic, non-spore-forming, Gram-positive bacilli, and rarely associated with human infections. Herein, we reported the first case of community-acquired pneumonia (CAP) and bacteremia due to Exiguobacterium spp. in China.Case presentationAn adult male with severe CAP was hospitalized. The pathogen was isolated from his bloodstream and broncho-alveolar lavage fluid. The correct identification of the micro-organism was achieved using 16S rRNA sequencing, and its antibiotic susceptibility test was performed by microdilution method. The Whole Genome Sequencing (WGS) was used to characterize its genetic features and to elucidate its potential pathogenic mechanisms. Furthermore, its genome sequence was also compared with those of 3 publicly-available Exiguobacterium strains. A PubMed search was performed for further understanding the features of Exiguobacterium infections. Phylogenetic analysis of the 16S rRNA gene sequence showed that the strain GX59 was most closely related to Exiguobacterium AT1b (99.7%). The genome of GX59 was 2,727,929 bp in size, harbouring 2855 putative protein-coding genes, 5 rRNA operons, 37 tRNA genes and 1 tmRNA. The multiple genome comparison of 4 Exiguobacterium strains demonstrated that Exiguobacterium contained 37 genes of secretion systems, including sec, tat, FEA, Type IV Pili and competence-related DNA transformation transporter (Com). Virulence factors of the micro-organism included tlyC, NprR, MCP, Dam, which might play a critical role in causing lethal infection.ConclusionsThe study highlighted the potential pathogenicity of the genus Exiguobacterium for its unique genes encoding various virulence factors and those associated with antibiotic resistance, therefore, its clinical significance should be valued.

A novel star-shaped copolymer TAPP-PLA-b-TPGS was synthesized as drug nanocarriers for cancer chemical and photodynamic combination therapy.

Purpose Community-associated Staphylococcus aureus (CA S. aureus ) is the most common causative pathogen of the skin and soft tissue infections (SSTIs). This study aims to determine clonal distribution, virulence factors of CA S. aureus clinical isolates from purulent SSTIs in Beijing, China. Materials and methods CA- S. aureus isolates were collected from 115 outpatients with purulent SSTIs from the department of dermatology from April 2015 to April 2017. Multilocus sequence typing and Staphylococcus cassette chromosome mec typing were performed to explore molecular characteristics. Phylogenetic analysis of 16S rRNA of dominant S. aureus isolates was performed using MEGA-X software. Virulence genes were detected by PCR, while biofilm formation was evaluated by a microtiter plate method. The antimicrobial susceptibility was tested by an automatic VITEK system. Results Forty-four CA- S. aureus isolates identified from SSTIs contain 9 methicillin-resistant S. aureus (MRSA) isolates (20.4%) and 35 methicillin-susceptible S. aureus isolates (MSSA) (79.6%). The dominant sequence types (STs) were ST22 (40.9%) and clonal complex 59 (CC59; 77.8%) in Community-associated methicillin resistant methicillin-resistant S. aureus . 27.8% of ST22 isolates were homologous to the epidemic ST22 EMRSA-15 in Europe. The prevalence of virulence genes lukS/lukF, tst-1, etA, edinA, icaA , and icaD was 50%, 93.2%, 4.5%, 4.5%, 100%, and 100%, respectively. All CC59 isolates exhibited stronger biofilm-forming capability than ST22 clones. Among the MSSA subgroup, the poor biofilm producers had significantly higher sensitivity to sulfamethoxazole/Trimethoprim. Conclusion The dominant epidemic clone PVL + ST22 MSSA containing tst-1 occurs in Beijing, indicating that a PVL + ST398 clone which was previously predominant in this district had been replaced by a new clone.

This study provides a deeper insight into horizontal transfer of resistance genes among IncN1 plasmids.