Conformational flexibility revealed by the crystal structure of a crenarchaeal RadA

Homologous recombinational repair is an essential mechanism for repair of double-strand breaks in DNA. Recombinases of the RecA-fold family play a crucial role in this process, forming filaments that utilize ATP to mediate their interactions with single- and double-stranded DNA. The recombinase molecules present in the archaea (RadA) and eukaryota (Rad51) are more closely related to each other than to their bacterial counterpart (RecA) and, as a result, RadA makes a suitable model for the eukaryotic system. The crystal structure of Sulfolobus solfataricus RadA has been solved to a resolution of 3.2 Å in the absence of nucleotide analogues or DNA, revealing a narrow filamentous assembly with three molecules per helical turn. As observed in other RecA-family recombinases, each RadA molecule in the filament is linked to its neighbour via interactions of a short β-strand with the neighbouring ATPase domain. However, despite apparent flexibility between domains, comparison with other structures indicates conservation of a number of key interactions that introduce rigidity to the system, allowing allosteric control of the filament by interaction with ATP. Additional analysis reveals that the interaction specificity of the five human Rad51 paralogues can be predicted using a simple model based on the RadA structure

What have we already learned from the CMB?

The COBE satellite, and the DMR experiment in particular, was extraordinarily successful. However, the DMR results were announced about 7 years ago, during which time a great deal more has been learned about anisotropies in the Cosmic Microwave Background (CMB). The CMB experiments currently being designed and built, including long-duration balloons, interferometers, and two space missions, promise to address several fundamental cosmological issues. We present our evaluation of what we already know, what we are beginning to learn now, and what the future may bring.Comment: 20 pages, 3 figures. Changes to match version accepted by PAS

Bioeconomic Model of Rainbow Trout (\u3cem\u3eOncorhynchus mykiss\u3c/em\u3e) and Humpback Chub (\u3cem\u3eGila cypha\u3c/em\u3e) Management in the Grand Canyon

The Colorado River, from Glen Canyon Dam (GCD) to the Little Colorado River (LCR) confluence, includes both non-native Rainbow Trout (Oncorhynchus mykiss) and endangered native Humpback Chub (Gila cypha). While both Rainbow Trout and Humpback Chub are valued fish species in this system, Rainbow Trout can have a negative effect on Humpback Chub survival. We developed a bioeconomic model to determine management actions that minimize the costs of controlling Rainbow Trout abundance subject to achieving Humpback Chub population goals. The model is compartmentalized into population and management components. The population component characterizes the stylized dynamics of Rainbow Trout and Humpback Chub from GCD to the LCR confluence within the Colorado River. The management component of the model identifies Rainbow Trout mechanical removal strategies that achieve average annual juvenile Humpback Chub survival targets while minimizing management costs. This research is an interdisciplinary effort combining biological models and economic methods to address federal, state and tribal stakeholder resource goals related to Rainbow Trout and Humpback Chub management in this complex social-ecological system

Correlates of serum lipoprotein (A) in children and adolescents in the United States. The third National Health Nutrition and Examination Survey (NHANES-III)

OBJECTIVE: To determine the correlates of serum lipoprotein (a) (Lp(a)) in children and adolescents in the United States. METHODS: Cross-sectional study using representative data from a US national sample for persons aged 4–19 years participating in The Third National Health Nutrition and Examination Survey (NHANES-III). RESULTS: We observed ethnicity-related differences in levels of Lp(a) > 30 mg/dl, with values being markedly higher in African American (black) than nonhispanic white (white) and Mexican American children in multivariate model (P < 0.001). Higher levels of Lp(a) > 30 mg/dl associated with parental history of body mass index and residence in metro compared to nonmetro in Blacks, and high birth weight in Mexican American children in the NHANES-III. In the entire group, total cholesterol (which included Lp(a)) and parental history of premature heart attack/angina before age 50 (P < 0.02) showed consistent, independent, positive association with Lp(a). In subgroup analysis, this association was only evident in white (P = 0.04) and black (P = 0.05) children. However, no such collective consistent associations of Lp(a) were found with age, gender, or birth weight. CONCLUSION: Ethnicity-related differences in mean Lp(a) exist among children and adolescents in the United States and parental history of premature heart attack/angina significantly associated with levels of Lp(a) in children. Further research on the associations of Lp(a) levels in childhood with subsequent risk of atherosclerosis is needed

Submission of structural biology data for review purposes.

The editors discuss the submission of structural biology data

The Extraordinary X-ray Light Curve of the Classical Nova V1494 Aquilae (1999 #2) in Outburst: The Discovery of Pulsations and a "Burst"

V1494 Aql (Nova Aql 1999 No. 2) was discovered on 2 December 1999. We obtained Chandra ACIS-I spectra on 15 April and 7 June 2000 which appear to show only emission lines. Our third observation, on 6 August, showed that its spectrum had evolved to that characteristic of a Super Soft X-ray Source. We then obtained Chandra LETG+HRC-S spectra on 28 September (8 ksec) and 1 October (17 ksec). We analyzed the X-ray light curve of our grating observations and found both a short time scale ``burst'' and oscillations. Neither of these phenomena have previously been seen in the light curve of a nova in outburst. The ``burst'' was a factor of 10 rise in X-ray counts near the middle of the second observation, and which lasted about 1000 sec; it exhibited at least two peaks, in addition to other structure. Our time series analysis of the combined 25 ksec observation shows a peak at 2500 s which is present in independent analyses of both the zeroth order image and the dispersed spectrum and is not present in similar analyses of grating data for HZ 43 and Sirius B. Further analyses of the V1494 Aql data find other periods present which implies that we are observing non-radial g+ modes from the pulsating, rekindled white dwarf.Comment: ApJ accepte

Immediate delivery compared with expectant management after preterm pre-labour rupture of the membranes close to term (PPROMT trial): a randomised controlled trial

Background Preterm pre-labour ruptured membranes close to term is associated with increased risk of neonatal infection, but immediate delivery is associated with risks of prematurity. The balance of risks is unclear. We aimed to establish whether immediate birth in singleton pregnancies with ruptured membranes close to term reduces neonatal infection without increasing other morbidity. Methods The PPROMT trial was a multicentre randomised controlled trial done at 65 centres across 11 countries. Women aged over 16 years with singleton pregnancies and ruptured membranes before the onset of labour between 34 weeks and 36 weeks and 6 days weeks who had no signs of infection were included. Women were randomly assigned (1:1) by a computer-generated randomisation schedule with variable block sizes, stratified by centre, to immediate delivery or expectant management. The primary outcome was the incidence of neonatal sepsis. Secondary infant outcomes included a composite neonatal morbidity and mortality indicator (ie, sepsis, mechanical ventilation ≥24 h, stillbirth, or neonatal death); respiratory distress syndrome; any mechanical ventilation; and duration of stay in a neonatal intensive or special care unit. Secondary maternal outcomes included antepartum or intrapartum haemorrhage, intrapartum fever, postpartum treatment with antibiotics, and mode of delivery. Women and caregivers could not be masked, but those adjudicating on the primary outcome were masked to group allocation. Analyses were by intention to treat. This trial is registered with the International Clinical Trials Registry, number ISRCTN44485060. Findings Between May 28, 2004, and June 30, 2013, 1839 women were recruited and randomly assigned: 924 to the immediate birth group and 915 to the expectant management group. One woman in the immediate birth group and three in the expectant group were excluded from the primary analyses. Neonatal sepsis occurred in 23 (2%) of 923 neonates whose mothers were assigned to immediate birth and 29 (3%) of 912 neonates of mothers assigned to expectant management (relative risk [RR] 0·8, 95% CI 0·5–1·3; p=0·37). The composite secondary outcome of neonatal morbidity and mortality occurred in 73 (8%) of 923 neonates of mothers assigned to immediate delivery and 61 (7%) of 911 neonates of mothers assigned to expectant management (RR 1·2, 95% CI 0·9–1·6; p=0·32). However, neonates born to mothers in the immediate delivery group had increased rates of respiratory distress (76 [8%] of 919 vs 47 [5%] of 910, RR 1·6, 95% CI 1·1–2·30; p=0·008) and any mechanical ventilation (114 [12%] of 923 vs 83 [9%] of 912, RR 1·4, 95% CI 1·0–1·8; p=0·02) and spent more time in intensive care (median 4·0 days [IQR 0·0–10·0] vs 2·0 days [0·0–7·0]; p<0·0001) compared with neonates born to mothers in the expectant management group. Compared with women assigned to the immediate delivery group, those assigned to the expectant management group had higher risks of antepartum or intrapartum haemorrhage (RR 0·6, 95% CI 0·4–0·9), intrapartum fever (0·4, 0·2–0·9), and use of postpartum antibiotics (0·8, 0·7–1·0), and longer hospital stay (p<0·0001), but a lower risk of caesarean delivery (RR 1·4, 95% CI 1·2–1·7). Interpretation In the absence of overt signs of infection or fetal compromise, a policy of expectant management with appropriate surveillance of maternal and fetal wellbeing should be followed in pregnant women who present with ruptured membranes close to term

Confirmation of SBS 1150+599A As An Extremely Metal-Poor Planetary Nebula

SBS 1150+599A is a blue stellar object at high galactic latitude discovered in the Second Byurakan Survey. New high-resolution images of SBS 1150+599A are presented, demonstrating that it is very likely to be an old planetary nebula in the galactic halo, as suggested by Tovmassian et al (2001). An H-alpha image taken with the WIYN 3.5-m telescope and its "tip/tilt" module reveals the diameter of the nebula to be 9.2", comparable to that estimated from spectra by Tovmassian et al. Lower limits to the central star temperature were derived using the Zanstra hydrogen and helium methods to determine that the star's effective temperature must be > 68,000K and that the nebula is optically thin. New spectra from the MMT and FLWO telescopes are presented, revealing the presence of strong [Ne V] lambda 3425, indicating that the central star temperature must be > 100,000K. With the revised diameter, new central star temperature, and an improved central star luminosity, we can constrain photoionization models for the nebula significantly better than before. Because the emission-line data set is sparse, the models are still not conclusive. Nevertheless, we confirm that this nebula is an extremely metal-poor planetary nebula, having a value for O/H that is less than 1/100 solar, and possibly as low as 1/500 solar.Comment: 19 pages, 6 figures. Accepted for publication in the Astronomical Journa

Amylin and beta amyloid proteins interact to form amorphous heterocomplexes with enhanced toxicity in neuronal cells

Human pancreatic islet amyloid polypeptide (hIAPP) and beta amyloid (Aβ) can accumulate in Type 2 diabetes (T2D) and Alzheimer’s disease (AD) brains and evidence suggests that interaction between the two amyloidogenic proteins can lead to the formation of heterocomplex aggregates. However, the structure and consequences of the formation of these complexes remains to be determined. The main objective of this study was to characterise the different types and morphology of Aβ-hIAPP heterocomplexes and determine if formation of such complexes exacerbate neurotoxicity. We demonstrate that hIAPP promotes Aβ oligomerization and formation of small oligomer and large aggregate heterocomplexes. Co-oligomerized Aβ42-hIAPP mixtures displayed distinct amorphous structures and a 3-fold increase in neuronal cell death as compared to Aβ and hIAPP alone. However, in contrast to hIAPP, non-amyloidogenic rat amylin (rIAPP) reduced oligomer Aβ-mediated neuronal cell death. rIAPP exhibited reductions in Aβ induced neuronal cell death that was independent of its ability to interact with Aβ and form heterocomplexes; suggesting mediation by other pathways. Our findings reveal distinct effects of IAPP peptides in modulating Aβ aggregation and toxicity and provide new insight into the potential pathogenic effects of Aβ-IAPP hetero-oligomerization and development of IAPP based therapies for AD and T2D

Structure of Tagatose-1,6-bisphosphate Aldolase. Insight into chiral discrimination, mechanism, and specificity of class II aldolases

Tagatose-1,6-bisphosphate aldolase (TBPA) is a tetrameric class II aldolase that catalyzes the reversible condensation of dihydroxyacetone phosphate with glyceraldehyde 3-phosphate to produce tagatose 1,6-bisphosphate. The high resolution (1.45 Å) crystal structure of the Escherichia coli enzyme, encoded by the agaY gene, complexed with phosphoglycolohydroxamate (PGH) has been determined. Two subunits comprise the asymmetric unit, and a crystallographic 2-fold axis generates the functional tetramer. A complex network of hydrogen bonds position side chains in the active site that is occupied by two cations. An unusual Na(+) binding site is created using a interaction with Tyr(183) in addition to five oxygen ligands. The catalytic Zn(2+) is five-coordinate using three histidine nitrogens and two PGH oxygens. Comparisons of TBPA with the related fructose-1,6-bisphosphate aldolase (FBPA) identifies common features with implications for the mechanism. Because the major product of the condensation catalyzed by the enzymes differs in the chirality at a single position, models of FBPA and TBPA with their cognate bisphosphate products provide insight into chiral discrimination by these aldolases. The TBPA active site is more open on one side than FBPA, and this contributes to a less specific enzyme. The availability of more space and a wider range of aldehyde partners used by TBPA together with the highly specific nature of FBPA suggest that TBPA might be a preferred enzyme to modify for use in biotransformation chemistry