Abstract Objective: To determine the size of reduction in homocysteine concentrations produced by dietary supplementation with folic acid and with vitamins B-12 or B-6. Design: Meta-analysis of ...randomised controlled trials that assessed the effects of folic acid based supplements on blood homocysteine concentrations. Multivariate regression analysis was used to determine the effects on homocysteine concentrations of different doses of folic acid and of the addition of vitamin B-12 or B-6. Subjects: Individual data on 1114 people included in 12 trials. Findings: The proportional and absolute reductions in blood homocysteine produced by folic acid supplements were greater at higher pretreatment blood homocysteine concentrations (P<0.001) and at lower pretreatment blood folate concentrations (P<0.001). After standardisation to pretreatment blood concentrations of homocysteine of 12 μmol/l and of folate of 12 nmol/l (approximate average concentrations for Western populations), dietary folic acid reduced blood homocysteine concentrations by 25% (95% confidence interval 23% to 28%; P<0.001), with similar effects in the range of 0.5-5 mg folic acid daily. Vitamin B-12 (mean 0.5 mg daily) produced an additional 7% (3% to 10%) reduction in blood homocysteine. Vitamin B-6 (mean 16.5 mg daily) did not have a significant additional effect. Conclusions: Typically in Western populations, daily supplementation with both 0.5-5 mg folic acid and about 0.5 mg vitamin B-12 would be expected to reduce blood homocysteine concentrations by about a quarter to a third (for example, from about 12 μmol/l to 8-9 μmol/l). Large scale randomised trials of such regimens in high risk populations are now needed to determine whether lowering blood homocysteine concentrations reduces the risk of vascular disease. Key messages Higher blood homocysteine concentrations seem to be associated with higher risks of occlusive vascular disease and with lower blood concentrations of folate and vitamins B-12 and B-6 Proportional and absolute reductions in blood homocysteine concentrations with folic acid supplements are greater at higher pretreatment blood homocysteine concentrations and at lower pretreatment blood folate concentrations In typical Western populations, supplementation with both 0.5-5 mg daily folic acid and about 0.5 mg daily vitamin B-12 should reduce blood homocysteine concentrations by about a quarter to a third Large scale randomised trials of such regimens in people at high risk are now needed to determine whether lowering blood homocysteine concentrations reduces the risk of vascular disease
MRE11 within the MRE11-RAD50-NBS1 (MRN) complex acts in DNA double-strand break repair (DSBR), detection, and signaling; yet, how its endo- and exonuclease activities regulate DSBR by nonhomologous ...end-joining (NHEJ) versus homologous recombination (HR) remains enigmatic. Here, we employed structure-based design with a focused chemical library to discover specific MRE11 endo- or exonuclease inhibitors. With these inhibitors, we examined repair pathway choice at DSBs generated in G2 following radiation exposure. While nuclease inhibition impairs radiation-induced replication protein A (RPA) chromatin binding, suggesting diminished resection, the inhibitors surprisingly direct different repair outcomes. Endonuclease inhibition promotes NHEJ in lieu of HR, while exonuclease inhibition confers a repair defect. Collectively, the results describe nuclease-specific MRE11 inhibitors, define distinct nuclease roles in DSB repair, and support a mechanism whereby MRE11 endonuclease initiates resection, thereby licensing HR followed by MRE11 exonuclease and EXO1/BLM bidirectional resection toward and away from the DNA end, which commits to HR.
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•Designed inhibitors specifically block MRE11 endo- or exonuclease activity•MRE11 endonuclease initiates resection, licensing repair by HR at two-ended DSBs•MRE11 exonuclease and EXO1/BLM resect bidirectionally toward and away from the DNA end•ssDNA formed by either 5′-3′ or 3′-5′ exonuclease activities commits to HR
Distribution, nymphal habitat and genetic structure of the New Zealand mayfly Isothraulus abditus were investigated to improve our understanding of its ecology and conservation status. A description ...of the undescribed subimaginal stage is also provided. Isothraulus abditus has now been recorded from 55 North Island streams, 47 being new to published literature. Its distribution currently extends from Mangonui in Northland to Taumatatahi near Whanganui. Nymphs live in forested stream pools and backwaters containing organic detritus. Genetic structure of six populations was assessed using the mitochondrial cytochrome c oxidase subunit I (COI) gene. Thirty-six haplotypes were identified from 123 individuals, and a maximum uncorrected genetic distance of 1.8% indicated that specimens belong to a single species. However, those within Northland showed some genetic differentiation. Restricted habitat, sparse distribution and some genetic differentiation of I. abditus suggest its conservation status should be classified as 'At Risk'.
LSID:
urn:lsid:zoobank.org:pub:75C386BC-C0A5-4627-AE4B-8C5D749D53BA
We present the first catalog of gamma-ray sources emitting above 56 and 100 TeV with data from the High Altitude Water Cherenkov Observatory, a wide field-of-view observatory capable of detecting ...gamma rays up to a few hundred TeV. Nine sources are observed above 56 TeV, all of which are likely galactic in origin. Three sources continue emitting past 100 TeV, making this the highest-energy gamma-ray source catalog to date. We report the integral flux of each of these objects. We also report spectra for three highest-energy sources and discuss the possibility that they are PeVatrons.
Plasma-wall interactions in a commercial-scale fusion power station may exert high transient thermal loads on plasma-facing surfaces, repeatedly subjecting underlying structural materials to high ...temperatures for short durations. Specimens of the reduced activation ferritic-martensitic steel Eurofer-97 were continuously aged at constant temperature in the range of 550°C to 950°C for up to 168 hours in a furnace to investigate the microstructural effects of short-term high temperature exposure. A CO2 laser was also used to repeatedly heat another specimen from 400°C to 850°C a total of 1,480 times over a period of 41 hours to explore transient heating effects. Microstructural changes were studied via scanning electron and focused ion beam microscopy and include (i) the coarsening of Cr-rich secondary phase precipitates when continuously heated above 750°C, (ii) an increase in average grain size above 800°C and (iii) the evolution of a new lath martensite microstructure above 850°C. Conversely, transient heating via a laser was found to result in the decomposition of the as-received lath martensite structure into ferrite and Cr-rich carbide precipitates, accompanied by a significant increase in average grain size from 0.1-2 µm to 5-40 µm. Experimental analysis was supported by thermodynamic simulation of the equilibrium phase behaviour of Eurofer-97 in MatCalc and thermal finite element modelling of plasma-wall interaction heating on the water-cooled lithium-lead tritium breeding blanket concept in Comsol Multiphysics. Simulated thermal transients were found to significantly alter the microstructure of Eurofer-97 and the implications of this are discussed.
Using solid, machined X-pinch targets driven by currents rising from 0 to 5-6 MA in 60 ns, we observed bright spots of 5-9-keV continuum radiation from 5±2-μm diameter regions. The >6-keV radiation ...is emitted in about 0.4 ns, and the bright spots are roughly 75 times brighter than the bright spots measured at 1 MA. A total x-ray power of 10 TW peak and yields of 165±20 kJ were emitted from a 3-mm height. The 3-5-keV continuum radiation had a 50-90-GW peak power and 0.15-0.35-kJ yield. The continuum is plausibly from a 1275±75-eV blackbody or alternatively from a 3500±500-eV bremsstrahlung source.
Babies who are small at birth or during infancy have increased rates of cardiovascular disease and non-insulin-dependent diabetes as adults. Some of these babies have low birthweights, some are small ...in relation to the size of their placentas, some are thin at birth, and some are short at birth and fail to gain weight in infancy. This paper shows how fetal undernutrition at different stages of gestation can be linked to these patterns of early growth. The fetuses' adaptations to undernutrition are associated with changes in the concentrations of fetal and placental hormones. Persisting changes in the levels of hormone secretion, and in the sensitivity of tissues to them, may link fetal undernutrition with abnormal structure, function, and disease in adult life.
Aim To measure the cumulative incidence of any retinopathy, maculopathy and sight‐threatening diabetic retinopathy (STDR), and calculate optimal screening intervals by retinopathy grade at baseline ...for patients with Type 1 diabetes attending an established systematic retinal screening programme.
Methods All patients with Type 1 diabetes registered with enrolled general practitioners, excluding only those attending an ophthalmologist, were studied if retinopathy data was available at baseline and at least one further screen event. Screening utilized non‐stereoscopic 3‐field mydriatic photography and modified Wisconsin grading. STDR was defined as moderate pre‐proliferative retinopathy or greater and/or significant maculopathy in any eye.
Results Patients (n = 501) underwent 2742 screen events. Cumulative incidence of STDR in patients without baseline retinopathy was 0.3% (95% CI 0.0–0.9) at 1 year, rising to 3.9% (1.4–5.4) at 5 years. Rates of progression to STDR in patients with background and mild pre‐proliferative retinopathy at 1 year were 3.6% (0.5–6.6) and 13.5% (4.2–22.7), respectively. Progression to STDR was greater in patients with a higher grade of baseline retinopathy (P = 0.001) or a longer disease duration (P = 0.003). For a 95% likelihood of remaining free of STDR, mean screening intervals by baseline status were: no retinopathy 5.7 (95% CI 3.5–7.6) years, background 1.3 (0.4–2.0) years and mild pre‐proliferative 0.4 (0–0.8) years.
Conclusions Screening at 2–3 year intervals, rather than annually, for patients without retinopathy in Type 1 diabetes is feasible because of the low risk of progression to STDR, and may result in significant cost savings for a screening programme. Patients with higher grades of retinopathy require screening at least annually or more frequent.
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