Y-family DNA polymerases and their role in tolerance of cellular DNA damage.

The past 15 years have seen an explosion in our understanding of how cells replicate damaged DNA and how this can lead to mutagenesis. The Y-family DNA polymerases lie at the heart of this process, which is commonly known as translesion synthesis. This family of polymerases has unique features that enable them to synthesize DNA past damaged bases. However, as they exhibit low fidelity when copying undamaged DNA, it is essential that they are only called into play when they are absolutely required. Several layers of regulation ensure that this is achieve

The ergogenic effect of beta-alanine combined with sodium bicarbonate on high-intensity swimming performance

We investigated the effect of beta-alanine (BA) alone (study A) and in combination with sodium bicarbonate (SB) (study B) on 100- and 200-m swimming performance. In study A, 16 swimmers were assigned to receive either BA (3.2 g·day−1 for 1 week and 6.4 g·day−1 for 4 weeks) or placebo (PL; dextrose). At baseline and after 5 weeks of supplementation, 100- and 200-m races were completed. In study B, 14 were assigned to receive either BA (3.2 g·day−1 for 1 week and 6.4 g·day−1 for 3 weeks) or PL. Time trials were performed once before and twice after supplementation (with PL and SB), in a crossover fashion, providing 4 conditions: PL-PL, PL-SB, BA-PL, and BA-SB. In study A, BA supplementation improved 100- and 200-m time-trial performance by 2.1% (p = 0.029) and 2.0% (p = 0.0008), respectively. In study B, 200-m time-trial performance improved in all conditions, compared with presupplementation, except the PL-PL condition (PL-SB, +2.3%; BA-PL, +1.5%; BA-SB, +2.13% (p < 0.05)). BA-SB was not different from BA-PL (p = 0.21), but the probability of a positive effect was 78.5%. In the 100-m time-trial, only a within-group effect for SB was observed in the PL-SB (p = 0.022) and BA-SB (p = 0.051) conditions. However, 6 of 7 athletes swam faster after BA supplementation. The probability of BA having a positive effect was 65.2%; when SB was added to BA, the probability was 71.8%. BA and SB supplementation improved 100- and 200-m swimming performance. The coingestion of BA and SB induced a further nonsignificant improvement in performance

β-alanine supplementation improves in-vivo fresh and fatigued skeletal muscle relaxation speed

Purpose: In fresh muscle, supplementation with the rate-limiting precursor of carnosine, β-alanine (BA), results in a decline in muscle half-relaxation time (HRT) potentially via alterations to calcium (Ca2+) handling. Accumulation of hydrogen cation (H+) has been shown to impact Ca2+ signalling during muscular contraction, carnosine has the potential to serve as a cytoplasmic regulator of Ca2+ and H+ coupling, since it binds to both ions. The present study examined the effect of BA supplementation on intrinsic in-vivo isometric knee extensor force production and muscle contractility in both fresh and fatigued human skeletal muscle assessed during voluntary and electrically evoked (nerve and superficial muscle stimulation) contractions. Methods: Twenty-three males completed two experimental sessions, pre- and post- 28 day supplementation with 6.4 g.day−1 of BA (n=12) or placebo (PLA; n=11). Isometric force was recorded during a series of voluntary and electrically evoked knee extensor contractions. Results: BA supplementation had no effect on voluntary or electrically  evoked isometric force production, or twitch electromechanical delay and time-to-peak tension. There was a significant decline in muscle HRT in fresh and fatigued muscle conditions  during both resting (3±13%; 19±26%) and potentiated (1±15%; 2±20%) twitch contractions. Conclusions: The mechanism for reduced HRT in fresh and fatigued skeletal muscle following BA supplementation is unclear. Due to the importance of muscle relaxation on total energy consumption, especially during short, repeated contractions, BA supplementation may prove to be beneficial in minimising contractile slowing induced by fatigue. Trial registration The trial is registered with Clinicaltrials.gov, ID number NCT02819505

Effects of beta-alanine supplementation on brain homocarnosine/carnosine signal and cognitive function: an exploratory study

Objectives: Two independent studies were conducted to examine the effects of 28 d of beta-alanine supplementation at 6.4 g d-1 on brain homocarnosine/carnosine signal in omnivores and vegetarians (Study 1) and on cognitive function before and after exercise in trained cyclists (Study 2). Methods: In Study 1, seven healthy vegetarians (3 women and 4 men) and seven age- and sex-matched omnivores undertook a brain 1H-MRS exam at baseline and after beta-alanine supplementation. In study 2, nineteen trained male cyclists completed four 20-Km cycling time trials (two pre supplementation and two post supplementation), with a battery of cognitive function tests (Stroop test, Sternberg paradigm, Rapid Visual Information Processing task) being performed before and after exercise on each occasion. Results: In Study 1, there were no within-group effects of beta-alanine supplementation on brain homocarnosine/carnosine signal in either vegetarians (p = 0.99) or omnivores (p = 0.27); nor was there any effect when data from both groups were pooled (p = 0.19). Similarly, there was no group by time interaction for brain homocarnosine/carnosine signal (p = 0.27). In study 2, exercise improved cognitive function across all tests (P0.05) of beta-alanine supplementation on response times or accuracy for the Stroop test, Sternberg paradigm or RVIP task at rest or after exercise. Conclusion: 28 d of beta-alanine supplementation at 6.4g d-1 appeared not to influence brain homocarnosine/ carnosine signal in either omnivores or vegetarians; nor did it influence cognitive function before or after exercise in trained cyclists

Influence of training status on high-intensity intermittent performance in response to β-alanine supplementation

Recent investigations have suggested that highly trained athletes may be less responsive to the ergogenic effects of β-alanine (BA) supplementation than recreationally active individuals due to their elevated muscle buffering capacity. We investigated whether training status influences the effect of BA on repeated Wingate performance. Forty young males were divided into two groups according to their training status (trained: T, and non-trained: NT cyclists) and were randomly allocated to BA and a dextrose-based placebo (PL) groups, providing four experimental conditions: NTPL, NTBA, TPL, TBA. BA (6.4 g day-1 ) or PL was ingested for 4 weeks, with participants completing four 30-s lower-body Wingate bouts, separated by 3 min, before and after supplementation. Total work done was significantly increased following supplementation in both NTBA (p = 0.03) and TBA (p = 0.002), and it was significantly reduced in NTPL (p = 0.03) with no difference for TPL (p = 0.73). BA supplementation increased mean power output (MPO) in bout 4 for the NTBA group (p = 0.0004) and in bouts 1, 2 and 4 for the TBA group (p ≤ 0.05). No differences were observed in MPO for NTPL and TPL. BA supplementation was effective at improving repeated high-intensity cycling performance in both trained and non-trained individuals, highlighting the efficacy of BA as an ergogenic aid for high-intensity exercise regardless of the training status of the individual

Tectonic and climatic controls on rift escarpments: Erosion and flexural rebound of the Dhofar passive margin (Gulf of Aden, Oman)

International audienceWe investigate the respective roles of climatic parameters and the flexural rigidity of the lithosphere in the erosion history and behavior of two adjacent rift escarpments along the northern coast of the Gulf of Aden, in Oman. At this 25 Myr old passive margin, we define a type 1 scarp, which is high, sharp-crested and has retreated 25-30 km inland from its master fault, and a type 2 scarp, which exhibits a more rounded profile, lower relief, and still coincides with its mapped normal fault trace. Since about 15 Ma, the margin has been seasonally affected by monsoon precipitation but with contrasting effects at the type 1 and type 2 escarpments depending on the position of the Intertropical Convergence Zone in the geologic past: during peak monsoon conditions, both scarps experienced heavy rainfall and runoff, whereas during monsoon-starved conditions (such as today), the type 2 scarp experienced a foggy, moist climate while the type 1 scarp remained much drier. In order to assess the relative effects of climate and flexural parameters on the present-day morphology of the Dhofar margin, we present onedimensional numerical models of erosion and flexure along two profiles representative of the type 1 and type 2 scarps. Unlike most surface process models previously published, where present-day topography is the only criterion by which to evaluate the quality of model outputs, model behavior here is additionally constrained by independent estimates of denudation provided by geological cross sections, well-defined fault traces, and other stratigraphic markers. The best fitting models indicate that the type 1 escarpment formed under relatively arid climatic conditions and was affected by significant erosion, recession and flexural uplift due to a low (7 km) effective elastic thickness. In contrast, the morphology of the type 2 fault scarp was smoothed by a more humid climate, but a high effective elastic thickness ( 15 km) prevented it from uplifting or receding. In addition, we show that the sedimentary load acting at the foot of the escarpments exerts significant influence on their morphological evolution, though this parameter is often neglected in other scarp evolution models

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Reduced response to IKr blockade and altered hERG1a/1b stoichiometryin human heart failure

Heart failure (HF) claims 250,000 lives per year in the US, and nearly half of these deaths are sudden and presumably due to ventricular tachyarrhythmias. QT interval and action potential (AP) prolongation are hallmark proarrhythmic changes in the failing myocardium, which potentially result from alterations in repolarizing potassium currents. Thus,we aimed to examinewhether decreased expression of the rapid delayed rectifier potassiumcurrent, IKr, contributes to repolarization abnormalities in human HF. Tomap functional IKr expression across the left ventricle (LV), we optically imaged coronary-perfused LV free wall from donor and end-stage failing human hearts. The LV wedge preparation was used to examine transmural AP durations at 80% repolarization (APD80), and treatment with the IKr-blocking drug, E-4031, was utilized to interrogate functional expression. We assessed the percent change in APD80 post-IKr blockade relative to baseline APD80 (&#916;APD80) and found that &#916;APD80s are reduced in failing versus donor hearts in each transmural region, with 0.35-, 0.43-, and 0.41-fold reductions in endo-, mid-, and epicardium, respectively (p = 0.008, 0.037, and 0.022). We then assessed hERG1 isoform gene and protein expression levels using qPCR and Western blot. While we did not observe differences in hERG1a or hERG1b gene expression between donor and failing hearts, we found a shift in the hERG1a:hERG1b isoform stoichiometry at the protein level. Computer simulations were then conducted to assess IKr block under E-4031 influence in failing and nonfailing conditions. Our results confirmed the experimental observations and E-4031-induced relative APD80 prolongationwas greater in normal conditions than in failing conditions, provided that the cellularmodel of HF included a significant downregulation of IKr. In humanHF, the response to IKr blockade is reduced, suggesting decreased functional IKr expression. This attenuated functional response is associated with altered hERG1a:hERG1b protein stoichiometry in the failing human LV, and failing cardiomyoctye simulations support the experimental findings. Thus, of IKr protein and functional expression may be important determinants of repolarization remodeling in the failing human LV.We thank the Translational Cardiovascular Biobank & Repository (TCBR) at Washington University for provision of donor/patient records. The TCBR is supported by the NIH/CTSA (UL1 TR000448), Children's Discovery Institute, and Richard J. Wilkinson Trust. We also thank the laboratory of Dr. Sakiyama-Elbert for the use of the StepOnePlus equipment We appreciate the critical feedback on the manuscript by Dr. Jeanne Nerbonne. This work has been supported by the National Heart, Lung & Blood Institute (NHLBI, R01 HL114395). K. Holzem has been supported by the American Heart Association (12PRE12050315) and the NHLBI (F30 HL114310).Holzem, KM.; Gómez García, JF.; Glukhov, AV.; Madden, EJ.; Koppel, AC.; Ewald, GA.; Trénor Gomis, BA.... (2016). Reduced response to IKr blockade and altered hERG1a/1b stoichiometryin human heart failure. Journal of Molecular and Cellular Cardiology. 96:82-92. https://doi.org/10.1016/j.yjmcc.2015.06.008S82929