Structure and stereochemistry of the base excision repair glycosylase MutY reveal a mechanism similar to retaining glycosidases.

MutY adenine glycosylases prevent DNA mutations by excising adenine from promutagenic 8-oxo-7,8-dihydroguanine (OG):A mismatches. Here, we describe structural features of the MutY active site bound to an azaribose transition state analog which indicate a catalytic role for Tyr126 and approach of the water nucleophile on the same side as the departing adenine base. The idea that Tyr126 participates in catalysis, recently predicted by modeling calculations, is strongly supported by mutagenesis and by seeing close contact between the hydroxyl group of this residue and the azaribose moiety of the transition state analog. NMR analysis of MutY methanolysis products corroborates a mechanism for adenine removal with retention of stereochemistry. Based on these results, we propose a revised mechanism for MutY that involves two nucleophilic displacement steps akin to the mechanisms accepted for 'retaining' O-glycosidases. This new-for-MutY yet familiar mechanism may also be operative in related base excision repair glycosylases and provides a critical framework for analysis of human MutY (MUTYH) variants associated with inherited colorectal cancer

Optimizing Sequence Coverage for a Moderate Mass Protein in Nano-Electrospray Ionization Quadrupole Time-of-Flight Mass Spectrometry

Sample pretreatment was optimized to obtain high sequence coverage for human serum albumin (HSA, 66.5 kDa) when using nano-electrospray ionization quadrupole time-of-flight mass spectrometry (nESI-Q-TOF-MS). Use of the final method with trypsin, Lys-C and Glu-C digests gave a combined coverage of 98.8%. The addition of peptide fractionation resulted in 99.7% coverage. These results were comparable to those obtained previously with matrixassisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). The sample pretreatment/nESI-Q-TOF-MS method was also used with collision-induced dissociation to analyze HSA digests and to identify peptides that could be employed as internal mass calibrants in future studies of modifications to HSA

Optimizing Sequence Coverage for a Moderate Mass Protein in Nano-Electrospray Ionization Quadrupole Time-of-Flight Mass Spectrometry

Sample pretreatment was optimized to obtain high sequence coverage for human serum albumin (HSA, 66.5 kDa) when using nano-electrospray ionization quadrupole time-of-flight mass spectrometry (nESI-Q-TOF-MS). Use of the final method with trypsin, Lys-C and Glu-C digests gave a combined coverage of 98.8%. The addition of peptide fractionation resulted in 99.7% coverage. These results were comparable to those obtained previously with matrixassisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). The sample pretreatment/nESI-Q-TOF-MS method was also used with collision-induced dissociation to analyze HSA digests and to identify peptides that could be employed as internal mass calibrants in future studies of modifications to HSA

Bronchopulmonary Dysplasia: Executive Summary of a Workshop

Comment in Bronchopulmonary Dysplasia: The Ongoing Search for One Definition to Rule Them All. [J Pediatr. 2018] Midlife crisis? In its 50th year, BPD redefines itself. [J Pediatr. 2018

Health-Related Quality of Life and All-Cause Mortality among Older Healthy Individuals in Australia and the United States:A Prospective Cohort Study

Published online: 3 January 2021PURPOSE: Previous research has demonstrated that lower health-related quality of life (HRQoL) is associated with higher morbidity and mortality, especially in-patient groups. The association of HRQoL with all-cause mortality in community samples requires further investigation. This study aimed to examine whether HRQoL predicts all-cause mortality in older healthy community-dwelling people from Australia and the United States (U.S.) enrolled in the Aspirin in Reducing Events in the Elderly (ASPREE) trial. We also explored whether this association varies by gender or country. METHOD: A prospective cohort of 19,106 individuals aged 65-98 years, who were without a dementia diagnosis or a known major life-limiting disease, and completed the 12-item short-form-HRQoL at recruitment (2010-2014). They were followed until June 2017. Cox proportional-hazard models were used to determine the association between the physical (PCS) and mental component scores (MCS) of HRQoL and all-cause mortality, adjusting for sociodemographic factors, health-related behaviours and clinical measures. Hazards ratios were estimated for every 10-unit increase in PCS or MCS. RESULTS: There were 1052 deaths over a median 4.7-years (interquartile range 3.6-5.7) of follow-up, with 11.9 events per 1000 person-years. Higher PCS was associated with lower all-cause mortality (HR 0.83, 95% CI 0.77, 0.89) in the entire sample, while higher MCS was associated with lower mortality among U.S. participants only (HR 0.78, 95% CI 0.63, 0.95). Gender differences in the association of either PCS or MCS with mortality were not observed. CONCLUSION: Our large study provides evidence that HRQoL is inversely associated with all-cause mortality among initially healthy older people.Aung Zaw Zaw Phyo, Joanne Ryan, David A. Gonzalez-Chica, Robyn L. Woods, Christopher M. Reid, Mark R. Nelson ... et al

HI in Arp72 and similarities with M51-type systems

We present neutral hydrogen (H{\sc i}) observations with the Giant Metrewave Radio Telescope ({\it GMRT}) of the interacting galaxies NGC5996 and NGC5994, which make up the Arp72 system. Arp72 is an M51-type system and shows a complex distribution of H{\sc i} tails and a bridge due to tidal interactions. H{\sc i} column densities ranging from 0.8$-1.8\times10^{20}$ atoms cm$^{-2}$ in the eastern tidal tail to 1.7$-2\times10^{21}$ atoms cm$^{-2}$ in the bridge connecting the two galaxies, are seen to be associated with star-forming regions. We discuss the morphological and kinematic similarities of Arp72 with M51, the archetypal example of the M51-type systems, and Arp86, another M51-type system studied with the {\it GMRT}, and suggest that a multiple passage model of Salo & Laurikainen may be preferred over the classical single passage model of Toomre & Toomre, to reproduce the H{\sc i} features in Arp72 as well as in other M-51 systems depicting similar optical and H{\sc i} features.Comment: 8 pages, 6 figures, accepted for publication in MNRA

Exploring impulsive solar magnetic energy release and particle acceleration with focused hard X-ray imaging spectroscopy

How impulsive magnetic energy release leads to solar eruptions and how those eruptions are energized and evolve are vital unsolved problems in Heliophysics. The standard model for solar eruptions summarizes our current understanding of these events. Magnetic energy in the corona is released through drastic restructuring of the magnetic field via reconnection. Electrons and ions are then accelerated by poorly understood processes. Theories include contracting loops, merging magnetic islands, stochastic acceleration, and turbulence at shocks, among others. Although this basic model is well established, the fundamental physics is poorly understood. HXR observations using grazing-incidence focusing optics can now probe all of the key regions of the standard model. These include two above-the-looptop (ALT) sources which bookend the reconnection region and are likely the sites of particle acceleration and direct heating. The science achievable by a direct HXR imaging instrument can be summarized by the following science questions and objectives which are some of the most outstanding issues in solar physics (1) How are particles accelerated at the Sun? (1a) Where are electrons accelerated and on what time scales? (1b) What fraction of electrons is accelerated out of the ambient medium? (2) How does magnetic energy release on the Sun lead to flares and eruptions? A Focusing Optics X-ray Solar Imager (FOXSI) instrument, which can be built now using proven technology and at modest cost, would enable revolutionary advancements in our understanding of impulsive magnetic energy release and particle acceleration, a process which is known to occur at the Sun but also throughout the Universe

Using Biomarkers to Inform Cumulative Risk Assessment

BACKGROUND: Biomarkers are considered the method of choice for determining exposure to environmental contaminants and relating such exposures to health outcomes. However, the association between many biomarkers and outcome is not direct because of variability in sensitivity and susceptibility in the individual. OBJECTIVES: We explore the relationship between environmental exposures and health outcomes as mitigated by differential susceptibility in individuals or populations and address the question “Can biomarkers enable us to understand and quantify better the population burden of disease and health effects attributable to environmental exposures?” METHODS: We use a case–study approach to develop the thesis that biomarkers offer a pathway to disaggregation of health effects into specific, if multiple, risk factors. We offer the point of view that a series or array of biomarkers, including biomarkers of exposure, biomarkers of susceptibility, and biomarkers of effect, used in concert offer the best means by which to effect this disaggregation. We commence our discussion by developing the characteristics of an ideal biomarker, then give some examples of commonly used biomarkers to show the strengths and weaknesses of current usage. We follow this by more detailed case-study assessment outlining the state-of-the-science in specific cases. We complete our work with recommendations regarding the future use of biomarkers and areas for continued development. CONCLUSIONS: The case studies provide examples of when and how biomarkers can be used to infer the source and magnitude of exposure among a set of competing sources and pathways. The answer to this question is chemical specific and relates to how well the biomarker matches the characteristics of an “ideal” biomarker–in particular ease of collection and persistence. The use of biomarkers in combination provides a better opportunity to disaggregate both source and pathway contributions

LKB1 is required for hepatic bile acid transport and canalicular membrane integrity in mice

LKB1 is a ‘master’ protein kinase implicated in the regulation of metabolism, cell proliferation, cell polarity and tumorigenesis. However, the long-term role of LKB1 in hepatic function is unknown. In the present study, it is shown that hepatic LKB1 plays a key role in liver cellular architecture and metabolism. We report that liver-specific deletion of LKB1 in mice leads to defective canaliculi and bile duct formation, causing impaired bile acid clearance and subsequent accumulation of bile acids in serum and liver. Concomitant with this, it was found that the majority of BSEP (bile salt export pump) was retained in intracellular pools rather than localized to the canalicular membrane in hepatocytes from LLKB1KO (liver-specific Lkb1-knockout) mice. Together, these changes resulted in toxic accumulation of bile salts, reduced liver function and failure to thrive. Additionally, circulating LDL (low-density lipoprotein)-cholesterol and non-esterified cholesterol levels were increased in LLKB1KO mice with an associated alteration in red blood cell morphology and development of hyperbilirubinaemia. These results indicate that LKB1 plays a critical role in bile acid homoeostasis and that lack of LKB1 in the liver results in cholestasis. These findings indicate a novel key role for LKB1 in the development of hepatic morphology and membrane targeting of canalicular proteins

Cross section measurements of 155,157Gd(n, γ) induced by thermal and epithermal neutrons

© SIF, Springer-Verlag GmbH Germany, part of Springer Nature 2019Neutron capture cross section measurements on 155Gd and 157Gd were performed using the time-of-flight technique at the n_TOF facility at CERN on isotopically enriched samples. The measurements were carried out in the n_TOF experimental area EAR1, at 185 m from the neutron source, with an array of 4 C6D6 liquid scintillation detectors. At a neutron kinetic energy of 0.0253 eV, capture cross sections of 62.2(2.2) and 239.8(8.4) kilobarn have been derived for 155Gd and 157Gd, respectively, with up to 6% deviation relative to values presently reported in nuclear data libraries, but consistent with those values within 1.6 standard deviations. A resonance shape analysis has been performed in the resolved resonance region up to 181 eV and 307 eV, respectively for 155Gd and 157Gd, where on average, resonance parameters have been found in good agreement with evaluations. Above these energies and up to 1 keV, the observed resonance-like structure of the cross section has been analysed and characterised. From a statistical analysis of the observed neutron resonances we deduced: neutron strength function of 2. 01 (28) × 10 - 4 and 2. 17 (41) × 10 - 4; average total radiative width of 106.8(14) meV and 101.1(20) meV and s-wave resonance spacing 1.6(2) eV and 4.8(5) eV for n + 155Gd and n + 157Gd systems, respectively.Peer reviewedFinal Accepted Versio