Most bacteriophages possess long tails, which serve as the conduit for genome delivery. We report the solution structure of the N-terminal domain of gpV, the protein comprising the major portion of the noncontractile phage tail tube. This structure is very similar to a previously solved tail tube protein from a contractile-tailed phage, providing the first direct evidence of an evolutionary connection between these 2 distinct types of phage tails. A remarkable structural similarity is also seen to Hcp1, a component of the bacterial type VI secretion system. The hexameric structure of Hcp1 and its ability to form long tubes are strikingly reminiscent of gpV when it is polymerized into a tail tube. These data coupled with other similarities between phage and type VI secretion proteins support an evolutionary relationship between these systems. Using Hcp1 as a model, we propose a polymerization mechanism for gpV involving several disorder-toorder transitions.NMR structure ͉ disordered regions ͉ macromolecular assembly

BACKGROUNDCauses of early infant growth restriction remain incompletely understood. Where vitamin D deficiency is common, vitamin D supplementation during pregnancy and lactation may improve fetal-infant growth and other birth outcomes.METHODSWe conducted a randomized, double-blind, placebo-controlled trial of maternal vitamin D supplementation from 17-24 weeks gestation until birth or 6 months postpartum. Participants were randomly allocated to five vitamin D and/or placebo supplementation groups: (A) 0 IU/week, (B) 4200 IU/week, (C) 16800 IU/week, or (D) 28000 IU/week in pregnancy, all with 0 IU/week postpartum; or, (E) 28000 IU/week in prenatal and postpartum periods. The primary outcome was length-for-age z-score at one year of age according to World Health Organization child growth standards.RESULTSAmong 1164 infants assessed at one year of age (90% of 1300 pregnancies), there were no differences across groups in length-for-age z-scores (mean ±standard deviation): A: -0.93 ±1.05, B: -1.11 ±1.12, C: -0.97 ±0.97, D: -1.06 ±1.07, E: -0.94 ±1.00 (p=0.23). Groups were similar with respect to other anthropometric measures, birth outcomes, and morbidity. Vitamin D had dose- dependent effects on maternal and infant serum 25-hydroxyvitamin D and calcium, maternal urinary calcium excretion, and maternal parathyroid hormone concentrations. No clinical adverse events were attributed to the vitamin D intervention. CONCLUSIONSIn a population with widespread prenatal vitamin D deficiency and fetal/infant growth restriction, maternal vitamin D supplementation from mid-pregnancy until birth or 6 months postpartum does not influence fetal or infant growth, and has no beneficial or harmful effects on numerous other birth and infant outcomes.

In this chapter, we describe the structure, assembly, function, and evolution of the long, noncontractile tail of the siphophages, which comprise ∼60% of the phages on earth. We place -particular emphasis on features that are conserved among all siphophages, and trace evolutionary connections between these phages and myophages, which possess long contractile tails. The large number of high-resolution structures of tail proteins solved recently coupled to studies of tail-related complexes by electron microscopy have provided many new insights in this area. In addition, the availability of thousands of phage and prophage genome sequences has allowed the delineation of several large families of tail proteins that were previously unrecognized. We also summarize current knowledge pertaining to the mechanisms by which siphophage tails recognize the bacterial cell surface and mediate DNA injection through the cell envelope. We show that phages infecting Gram-positive and Gram-negative bacteria possess distinct families of proteins at their tail tips that are involved in this process. Finally, we speculate on the evolutionary advantages provided by long phage tails.

BackgroundFollowing independence from the Soviet Union in 1991, Estonia introduced a national insurance system, consolidated the number of health care providers, and introduced family medicine centred primary health care (PHC) to strengthen the health system.MethodsUsing routinely collected health billing records for 2005–2012, we examine health system utilisation for seven ambulatory care sensitive conditions (ACSCs) (asthma, chronic obstructive pulmonary disease [COPD], depression, Type 2 diabetes, heart failure, hypertension, and ischemic heart disease [IHD]), and by patient characteristics (gender, age, and number of co–morbidities). The data set contained 552 822 individuals. We use patient level data to test the significance of trends, and employ multivariate regression analysis to evaluate the probability of inpatient admission while controlling for patient characteristics, health system supply–side variables, and PHC use.FindingsOver the study period, utilisation of PHC increased, whilst inpatient admissions fell. Service mix in PHC changed with increases in phone, email, nurse, and follow–up (vs initial) consultations. Healthcare utilisation for diabetes, depression, IHD and hypertension shifted to PHC, whilst for COPD, heart failure and asthma utilisation in outpatient and inpatient settings increased. Multivariate regression indicates higher probability of inpatient admission for males, older patient and especially those with multimorbidity, but protective effect for PHC, with significantly lower hospital admission for those utilising PHC services.InterpretationOur findings suggest health system reforms in Estonia have influenced the shift of ACSCs from secondary to primary care, with PHC having a protective effect in reducing hospital admissions.

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Evolutionary relationships may exist among very diverse groups of proteins even though they perform different functions and display little sequence similarity. The tailed bacteriophages present a uniquely amenable system for identifying such groups because of their huge diversity yet conserved genome structures. In this work, we used structural, functional, and genomic context comparisons to conclude that the head–tail connector protein and tail tube protein of bacteriophage λ diverged from a common ancestral protein. Further comparisons of tertiary and quaternary structures indicate that the baseplate hub and tail terminator proteins of bacteriophage may also be part of this same family. We propose that all of these proteins evolved from a single ancestral tail tube protein fold, and that gene duplication followed by differentiation led to the specialized roles of these proteins seen in bacteriophages today. Although this type of evolutionary mechanism has been proposed for other systems, our work provides an evolutionary mechanism for a group of proteins with different functions that bear no sequence similarity. Our data also indicate that the addition of a structural element at the N terminus of the λ head–tail connector protein endows it with a distinctive protein interaction capability compared with many of its putative homologues.

IntroductionIn 2016, 2.6 million children died during their first month of life. We assessed the effectiveness of an integrated neonatal care kit (iNCK) on neonatal survival and other health outcomes in rural Pakistan.MethodsWe conducted a community-based, cluster randomised, pragmatic, open-label, controlled intervention trial in Rahim Yar Khan, Punjab, Pakistan. Clusters, 150 villages and their lady health workers (LHWs), were randomly assigned to deliver the iNCK (intervention) or standard of care (control). In intervention clusters, LHWs delivered the iNCK and education on its use to pregnant women. The iNCK contained a clean birth kit, chlorhexidine, sunflower oil, a continuous temperature monitor (ThermoSpot), a heat reflective blanket and reusable heat pack. LHWs were also given a hand-held scale. The iNCK was implemented primarily by caregivers. The primary outcome was all-cause neonatal mortality. Outcomes are reported at the individual level, adjusted for cluster allocation. Enrolment took place between April 2014 and July 2015 and participant follow-up concluded in August 2015.Results5451 pregnant women (2663 and 2788 in intervention and control arms, respectively) and their 5286 liveborn newborns (2585 and 2701 in intervention and control arms, respectively) were enrolled. 147 newborn deaths were reported, 65 in the intervention arm (25.4 per 1000 live births) compared with 82 in the control arm (30.6 per 1000 live births). Neonatal mortality was not significantly different between treatment groups (risk ratio 0.83, 95% CI 0.58 – 1.18; p = 0.30).ConclusionProviding co-packaged interventions directly to women did not significantly reduce neonatal mortality. Further research is needed to improve compliance with intended iNCK use.