Chlorination and oxidation of heparin and hyaluronan by hypochlorous acid and hypochlorite anions: effect of sulfate groups on reaction pathways and kinetics.

Hypochlorous acid (HOCl), produced in inflammatory conditions by the enzyme myeloperoxidase, and its anion hypochlorite (OCl(-)) exist in vivo at almost equal concentrations. Their reactions with hyaluronan and heparin (as a model for sulfated glycosaminoglycans in the extracellular matrix) have been studied as a function of pH. The major product in these reactions is the chloramide derivative of the glycosaminoglycans. Spectral, chloramide yield, and kinetic measurements show sharply contrasting behavior of heparin and hyaluronan and the data allow the calculation of second-order rate constants for the reactions of both HOCl and OCl(-) for all reaction pathways leading to the formation of chloramides and also oxidation products. By comparison with hyaluronan, it can be demonstrated that both N-sulfate and O-sulfate groups in heparin influence the proportions of these pathways in this glycosaminoglycan. Evidence is also given for further oxidation pathways involving a reaction of HOCl with the chloramide product of hyaluronan but not with heparin. The significance of these results for the mechanisms of inflammation, particularly for fragmentation of extracellular matrix glycosaminoglycans, is discussed

Objectively measured physical activity and kidney function in older men; a cross-sectional population-based study.

Background: kidney function declines in older adults and physical activity levels are low. We investigated whether higher levels of physical activity and lower levels of sedentary behaviour were associated with lower odds of low kidney function in older men. Methods: cross-sectional study of 1,352 men from the British Regional Heart Study, mean (standard deviation) age 78.5 (4.6) year. Physical activity and sedentary behaviour were measured using Actigraph GT3X accelerometers. Kidney function was measured by estimated Glomerular filtration rate (eGFR) using the chronic kidney disease-EPI creatinine-cystatin equation. Associations between physical (in)activity and kidney function were investigated using regression models. Results: higher levels of physical activity and lower levels of sedentary behaviour were associated with reduced odds ratios (ORs) for lower eGFR (<45 versus ≥45 ml/min per 1.73 m2) after adjustment for covariates. Each additional 1,000 steps, 30 min of light physical activity and 10 min of moderate/vigorous physical activity per day were associated with a lower odds (95% confidence interval (CI)) of a low eGFR; OR 0.81 (0.73, 0.91), OR 0.87 (0.78, 0.97) and OR 0.84 (0.76, 0.92), respectively. Each additional 30 min of sedentary behaviour per day was associated with a higher odds of a low eGFR (1.16 95% CI 1.06, 1.27). Associations between moderate/vigorous physical activity and lower kidney function persisted after adjustment for light physical activity or sedentary behaviour. Conclusion: physical activity is associated with kidney function in older men and could be of public health importance in this group who are at increased risk of poor kidney function and low physical activity. More evidence is needed on whether the association is causal

Does total volume of physical activity matter more than pattern for onset of CVD? A prospective cohort study of older British men.

AIMS: With increasing age, physical inactivity and sedentary behaviour levels increase, as does cardiovascular disease (CVD) incidence. We investigate how device-measured sedentary behaviour and physical activity (PA) are related to CVD onset in men aged 70+; whether the total volume of activity is more important than pattern. METHODS AND RESULTS: Prospective population-based cohort study of men recruited from 24 UK General Practices in 1978-80. In 2010-12, 3137 survivors were invited to complete questionnaires and wear an Actigraph GT3x accelerometer for 7 days. PA intensity was categorised as sedentary, light and moderate to vigorous (MVPA). Men were followed up for Myocardial Infarction, stroke and heart failure (ICD9 410-414, 430-438 and 428) morbidity and mortality from 2010 to 12 to June 2016. Hazard Ratios (HRs) for incident Cardiovascular Disease (CVD) were estimated. 1528/3137 (49%) men had sufficient accelerometer data. 254 men with pre-existing CVD were excluded. Participants' mean age was 78.4 (range 71-92) years. After median 4.9 years follow-up, 122 first CVD events occurred in 1181 men (22.7/1000 person-years) with complete data. For each additional 30 min in sedentary behaviour, light PA,10 min in MVPA, or 1000 steps/day, HRs for CVD were 1.09(95%CI 1.00, 1.19), 0.94(0.85, 1.04), 0.88(0.81, 0.96) and 0.86(0.78 to 0.95) respectively, adjusted for measurement-related factors, socio-demographics, health behaviours and disability. HRs for accumulating 150 min/week MVPA in bouts ≥1 min and bouts ≥10 min were 0.47(0.32 to 0.69), and 0.49(0.25, 0.98). CONCLUSIONS: In older men, high volume of steps or MVPA rather than MVPA bouts was associated with reduced CVD risk

Independent external validation of the QRISK3 cardiovascular disease risk prediction model using UK Biobank

Objective To externally evaluate the performance of QRISK3 for predicting 10 year risk of cardiovascular disease (CVD) in the UK Biobank cohort. Methods We used data from the UK Biobank, a large-scale prospective cohort study of 403 370 participants aged 40–69 years recruited between 2006 and 2010 in the UK. We included participants with no previous history of CVD or statin treatment and defined the outcome to be the first occurrence of coronary heart disease, ischaemic stroke or transient ischaemic attack, derived from linked hospital inpatient records and death registrations. Results Our study population included 233 233 women and 170 137 men, with 9295 and 13 028 incident CVD events, respectively. Overall, QRISK3 had moderate discrimination for UK Biobank participants (Harrell’s C-statistic 0.722 in women and 0.697 in men) and discrimination declined by age (<0.62 in all participants aged 65 years or older). QRISK3 systematically overpredicted CVD risk in UK Biobank, particularly in older participants, by as much as 20%. Conclusions QRISK3 had moderate overall discrimination in UK Biobank, which was best in younger participants. The observed CVD risk for UK Biobank participants was lower than that predicted by QRISK3, particularly for older participants. It may be necessary to recalibrate QRISK3 or use an alternate model in studies that require accurate CVD risk prediction in UK Biobank

High-throughput, quantitative analyses of genetic interactions in E. coli.

Large-scale genetic interaction studies provide the basis for defining gene function and pathway architecture. Recent advances in the ability to generate double mutants en masse in Saccharomyces cerevisiae have dramatically accelerated the acquisition of genetic interaction information and the biological inferences that follow. Here we describe a method based on F factor-driven conjugation, which allows for high-throughput generation of double mutants in Escherichia coli. This method, termed genetic interaction analysis technology for E. coli (GIANT-coli), permits us to systematically generate and array double-mutant cells on solid media in high-density arrays. We show that colony size provides a robust and quantitative output of cellular fitness and that GIANT-coli can recapitulate known synthetic interactions and identify previously unidentified negative (synthetic sickness or lethality) and positive (suppressive or epistatic) relationships. Finally, we describe a complementary strategy for genome-wide suppressor-mutant identification. Together, these methods permit rapid, large-scale genetic interaction studies in E. coli

The influence of pre-radiation salivary flow rates and radiation dose on parotid salivary gland dysfunction in patients receiving radiotherapy for head and neck cancers

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72238/1/j.1754-4505.1998.tb00913.x.pd

Single-atom imaging of fermions in a quantum-gas microscope

Single-atom-resolved detection in optical lattices using quantum-gas microscopes has enabled a new generation of experiments in the field of quantum simulation. Fluorescence imaging of individual atoms has so far been achieved for bosonic species with optical molasses cooling, whereas detection of fermionic alkaline atoms in optical lattices by this method has proven more challenging. Here we demonstrate single-site- and single-atom-resolved fluorescence imaging of fermionic potassium-40 atoms in a quantum-gas microscope setup using electromagnetically-induced-transparency cooling. We detected on average 1000 fluorescence photons from a single atom within 1.5s, while keeping it close to the vibrational ground state of the optical lattice. Our results will enable the study of strongly correlated fermionic quantum systems in optical lattices with resolution at the single-atom level, and give access to observables such as the local entropy distribution and individual defects in fermionic Mott insulators or anti-ferromagnetically ordered phases.Comment: 7 pages, 5 figures; Nature Physics, published online 13 July 201

The fraction of activated N-methyl-d-Aspartate receptors during synaptic transmission remains constant in the presence of the glutamate release inhibitor riluzole

Excessive N-methyl-d-aspartate (NMDA) receptor activation is widely accepted to mediate calcium-dependent glutamate excitotoxicity. The uncompetitive, voltage-dependent NMDA receptor antagonist memantine has been successfully used clinically in the treatment of neurodegenerative dementia and is internationally registered for the treatment of moderate to severe Alzheimer′s disease. Glutamate release inhibitors (GRIs) may also be promising for the therapy of some neurodegenerative diseases. During the clinical use of GRIs, it could be questioned whether there would still be a sufficient number of active NMDA receptors to allow any additional effects of memantine or similar NMDA receptor antagonists. To address this question, we determined the fraction of NMDA receptors contributing to postsynaptic events in the presence of therapeutically relevant concentrations of the GRI riluzole (1 μM) using an in vitro hippocampal slice preparation. We measured the charge transfer of pharmacologically isolated excitatory synaptic responses before and after the application of the selective, competitive NMDA receptor antagonist D-AP5 (100 μM). The fraction of activated NMDA receptors under control conditions did not differ from those in the presence of riluzole. It is therefore likely that NMDA receptor antagonists would be able to exert additional therapeutic effects in combination therapy with GRIs

Intercolony variation in reproductive skipping in the African penguin

This is the final version. Available on open access from Wiley via the DOI in this recordData availability statement: The data underlying this article are available in the Dryad digital repository: https://doi.org/10.5061/dryad.0rxwdbs3z (Leith et al., 2022).In long-lived species, reproductive skipping is a common strategy whereby sexually mature animals skip a breeding season, potentially reducing population growth. This may be an adaptive decision to protect survival, or a non-adaptive decision driven by individual-specific constraints. Understanding the presence and drivers of reproductive skipping behavior can be important for effective population management, yet in many species such as the endangered African penguin (Spheniscus demersus), these factors remain unknown. This study uses multistate mark-recapture methods to estimate African penguin survival and breeding probabilities at two colonies between 2013 and 2020. Overall, survival (mean ± SE) was higher at Stony Point (0.82 ± 0.01) than at Robben Island (0.77 ± 0.02). Inter-colony differences were linked to food availability; under decreasing sardine (Sardinops sagax) abundance, survival decreased at Robben Island and increased at Stony Point. Additionally, reproductive skipping was evident across both colonies; at Robben Island the probability of a breeder becoming a nonbreeder was ~0.22, versus ~0.1 at Stony Point. Penguins skipping reproduction had a lower probability of future breeding than breeding individuals; this lack of adaptive benefit suggests reproductive skipping is driven by individual-specific constraints. Lower survival and breeding propensity at Robben Island places this colony in greater need of conservation action. However, further research on the drivers of inter-colony differences is needed.Association of Zoos and AquariumsBristol Zoological SocietyDepartment of Forestry, Fisheries, and the EnvironmentEarthwatch InstitutePew Charitable TrustsLeiden Conservation FoundationSANCCOBSan Diego Zoo Wildlife Allianc