7-Deazaguanine modifications protect phage DNA from host restriction systems

Genome modifications are central components of the continuous arms race between viruses and their hosts. The archaeosine base (G+), which was thought to be found only in archaeal tRNAs, was recently detected in genomic DNA of Enterobacteria phage 9g and was proposed to protect phage DNA from a wide variety of restriction enzymes. In this study, we identify three additional 2′-deoxy-7-deazaguanine modifications, which are all intermediates of the same pathway, in viruses: 2′-deoxy-7-amido-7-deazaguanine (dADG), 2′-deoxy-7-cyano-7-deazaguanine (dPreQ0) and 2′-deoxy-7- aminomethyl-7-deazaguanine (dPreQ1). We identify 180 phages or archaeal viruses that encode at least one of the enzymes of this pathway with an overrepresentation (60%) of viruses potentially infecting pathogenic microbial hosts. Genetic studies with the Escherichia phage CAjan show that DpdA is essential to insert the 7-deazaguanine base in phage genomic DNA and that 2′-deoxy-7-deazaguanine modifications protect phage DNA from host restriction enzymes

Randomized Clinical Trial of High-Dose Rifampicin With or Without Levofloxacin Versus Standard of Care for Pediatric Tuberculous Meningitis: The TBM-KIDS Trial

Background. Pediatric tuberculous meningitis (TBM) commonly causes death or disability. In adults, high-dose rifampicin may reduce mortality. The role of fluoroquinolones remains unclear. There have been no antimicrobial treatment trials for pediatric TBM. Methods. TBM-KIDS was a phase 2 open-label randomized trial among children with TBM in India and Malawi. Participants received isoniazid and pyrazinamide plus: (i) high-dose rifampicin (30 mg/kg) and ethambutol (R30HZE, arm 1); (ii) high-dose rifampicin and levofloxacin (R30HZL, arm 2); or (iii) standard-dose rifampicin and ethambutol (R15HZE, arm 3) for 8 weeks, followed by 10 months of standard treatment. Functional and neurocognitive outcomes were measured longitudinally using Modified Rankin Scale (MRS) and Mullen Scales of Early Learning (MSEL). Results. Of 2487 children prescreened, 79 were screened and 37 enrolled. Median age was 72 months; 49%, 43%, and 8% had stage I, II, and III disease, respectively. Grade 3 or higher adverse events occurred in 58%, 55%, and 36% of children in arms 1, 2, and 3, with 1 death (arm 1) and 6 early treatment discontinuations (4 in arm 1, 1 each in arms 2 and 3). By week 8, all children recovered to MRS score of 0 or 1. Average MSEL scores were significantly better in arm 1 than arm 3 in fine motor, receptive language, and expressive language domains (P < .01). Conclusions. In a pediatric TBM trial, functional outcomes were excellent overall. The trend toward higher frequency of adverse events but better neurocognitive outcomes in children receiving high-dose rifampicin requires confirmation in a larger trial. Clinical Trials Registration. NCT02958709

Coordinated Control Strategies for a Permanent Magnet Synchronous Generator Based Wind Energy Conversion System

In this paper, a novel co-ordinated hybrid maximum power point tracking (MPPT)-pitch angle based on a radial basis function network (RBFN) is proposed for a variable speed variable pitch wind turbine. The proposed controller is used to maximise output power when the wind speed is low and optimise the power when the wind speed is high. The proposed controller provides robustness to the nonlinear characteristic of wind speed. It uses wind speed, generator speed, and generator power as input variables and utilises the duty cycle and the reference pitch angle as the output control variables. The duty cycle is used to control the converter so as to maximise the power output and the reference pitch angle is used to control the generator speed in order to control the generator output power in the above rated wind speed region. The effectiveness of the proposed controller was verified using MATLAB/Simulink software

The Effect of Mode of Delivery on Breastfeeding Outcomes: A Hospital Based Study

Background: Some studies suggested that a high rate of caesarean deliveries results in suboptimal breastfeeding outcomes. The relationship between mode of delivery and breastfeeding outcomes has been considered important given the rising prevalence of caesarean deliveries globally. The present study is to examine the relationship of mode of delivery with breastfeeding outcomes. Materials and Methods: This study was conducted at PSG Institute of Medical Science and Research, Coimbatore in the month of July 2018. Ethical clearance was obtained from the institution prior to the study. Chi square test was done to assess the association between socio-demographic variables, timely initiation of breastfeeding and exclusive breastfeeding with mode of delivery. The effect of caesarean on duration of breastfeeding was obtained by applying Kaplan-Meier method. Result: Prevalence ofcaesarean delivery was 36.2% and of vaginal delivery was 63.8%. A statistically significant association was obtained between caesarean deliveries and timely initiation of breastfeeding. However mode of delivery was not significantly associated with exclusive breastfeeding and duration of breastfeeding. Conclusion: The findings of our study indicates that caesarean deliveries have been associated with lower timely initiation n rates compared to vaginal deliveries

Factors Associated with Timely Initiation of Breast Feeding: a Hospital Based Study

Background: Early or timely initiation of breastfeeding, specifically within 1 h of birth, refers to the best practice recommendation by the World Health Organization (WHO). Timely initiation of breastfeeding has the potential to prevent 22 % of neonatal deaths if all infants were breastfed within an hour after birth [1]. The primary objective of the paper is to estimate the prevalence of breast feeding initiation within first hour of life and the clinical correlates and socio demographic factors. Material and methods: This study was conducted at PSG Institute of Medical Science and Research, Coimbatore in the month of July 2018. Mothers with the children age below four years attending paediatric outpatient department were included in the study. Multivariate logistic analysis was usedto determine the factors associated with timely initiation breastfeeding practice. Results: The prevalence of timely initiation of breastfeeding within one hour was 56.5%. It was observed that the caesarean delivery, preterm delivery, sick condition of the baby, earlier breast surgery, lack of counselling after delivery and lack of skin to skin contact at birth were negatively associated with timely initiation of breastfeeding within one hour. Conclusion: The findings clearly indicated that nearly half of the mothers did not initiate breastfeeding within one hour of birth

Escherichia coli BarA-UvrY regulates the pks island and kills Staphylococci via the genotoxin colibactin during interspecies competition

Wound infections are often polymicrobial in nature, biofilm associated and therefore tolerant to antibiotic therapy, and associated with delayed healing. Escherichia coli and Staphylococcus aureus are among the most frequently cultured pathogens from wound infections. However, little is known about the frequency or consequence of E. coli and S. aureus polymicrobial interactions during wound infections. Here we show that E. coli kills Staphylococci, including S. aureus, both in vitro and in a mouse excisional wound model via the genotoxin, colibactin. Colibactin biosynthesis is encoded by the pks locus, which we identified in nearly 30% of human E. coli wound infection isolates. While it is not clear how colibactin is released from E. coli or how it penetrates target cells, we found that the colibactin intermediate N-myristoyl-D-Asn (NMDA) disrupts the S. aureus membrane. We also show that the BarA-UvrY two component system (TCS) senses the environment created during E. coli and S. aureus mixed species interaction, leading to upregulation of pks island genes. Further, we show that BarA-UvrY acts via the carbon storage global regulatory (Csr) system to control pks expression. Together, our data demonstrate the role of colibactin in interspecies competition and show that it is regulated by BarA-UvrY TCS during interspecies competition

Discovery of novel bacterial queuine salvage enzymes and pathways in human pathogens

International audienceQueuosine (Q) is a complex tRNA modification widespread in eukaryotes and bacteria that contributes to the efficiency and accuracy of protein synthesis. Eukaryotes are not capable of Q synthesis and rely on salvage of the queuine base (q) as a Q precursor. While many bacteria are capable of Q de novo synthesis, salvage of the prokaryotic Q precursors preQ0 and preQ1 also occurs. With the exception of Escherichia coli YhhQ, shown to transport preQ0 and preQ1, the enzymes and transporters involved in Q salvage and recycling have not been well described. We discovered and characterized 2 Q salvage pathways present in many pathogenic and commensal bacteria. The first, found in the intracellular pathogen Chlamydia trachomatis, uses YhhQ and tRNA guanine transglycosylase (TGT) homologs that have changed substrate specificities to directly salvage q, mimicking the eukaryotic pathway. The second, found in bacteria from the gut flora such as Clostridioides difficile, salvages preQ1 from q through an unprecedented reaction catalyzed by a newly defined subgroup of the radical-SAM enzyme family. The source of q can be external through transport by members of the energy-coupling factor (ECF) family or internal through hydrolysis of Q by a dedicated nucleosidase. This work reinforces the concept that hosts and members of their associated microbiota compete for the salvage of Q precursors micronutrients