1,970 research outputs found
Phospho-dependent interactions between NBS1 and MDC1 mediate chromatin retention of the MRN complex at sites of DNA damage
Mammalian cells respond to DNA double-strand breaks (DSBs) by recruiting DNA repair and cell-cycle checkpoint proteins to such sites. Central to these DNA damage response (DDR) events is the DNA damage mediator protein MDC1. MDC1 interacts with several DDR proteins, including the MRE11–RAD50–NBS1 (MRN) complex. Here, we show that MDC1 is phosphorylated on a cluster of conserved repeat motifs by casein kinase 2 (CK2). Moreover, we establish that this phosphorylation of MDC1 promotes direct, phosphorylation-dependent interactions with NBS1 in a manner that requires the closely apposed FHA and twin BRCT domains in the amino terminus of NBS1. Finally, we show that these CK2-targeted motifs in MDC1 are required to mediate NBS1 association with chromatin-flanking sites of unrepaired DSBs. These findings provide a molecular explanation for the MDC1–MRN interaction and yield insights into how MDC1 coordinates the focal assembly and activation of several DDR factors in response to DNA damage
Aspirin desensitization in patients undergoing percutaneous coronary intervention: A survey of current practice
Background: Aspirin remains the mainstay of anti-platelet therapy in cardiac patients.However, if a patient is allergic to aspirin and dual anti-platelet therapy is indicated — suchas with percutaneous coronary intervention (PCI), then there is no clear guidance. Onepossibility is aspirin desensitization. A variety of protocols exist for the rapid desensitization ofpatients with aspirin allergy. The aim of this survey was to assess current knowledge andpractice regarding aspirin desensitization in the UK.Methods and results: We conducted a UK wide survey of all UK 116 PCI centers andobtained complete responses from 40 (35.4%) centers. Of these, just 7 (17.5%) centers hadpreviously desensitised patients; 29 (87.9%) centers suggested a lack of a local protocolprevented them from desensitizing, with 10 (30.3%) unsure of how to conduct desensitization.Only 5 (12.5%) centers had a local policy for aspirin desensitization although 25 (64.1%)units had a clinical strategy for dealing with aspirin allergy; the majority (72%) giving higherdoses of thienopyridine class drugs.Conclusions: In the UK, there appears to be no consistent approach to patients with aspirinallergy. Patients undergoing PCI benefit from dual anti-platelet therapy (including aspirin),and aspirin desensitization in those with known allergy may facilitate this. Sustained effortshould be placed on encouraging UK centers to use desensitization as a treatment modalityprior to PCI rather than avoiding aspirin altogether
The effect of soy phytoestrogen supplementation on thyroid status and cardiovascular risk markers in patients with subclinical hypothyroidism: A randomized, double-blind, crossover study
Context: There is concern whether soy phytoestrogens may affect thyroid function. If true, soy phytoestrogens may be expected to have a greater impact in subjects with subclinical hypothyroidism. Objective: The primary aim was to determine the effect of soy phytoestrogen supplementation on thyroid function, with a secondary aim of assessing the effects on cardiovascular risk indices in patients with subclinical hypothyroidism. Design and Setting: We conducted a randomized, double-blind, crossover study in a tertiary care setting. Participants: Sixty patients with subclinical hypothyroidism participated in the study. Intervention: Patients were randomly assigned to either low-dose phytoestrogen (30 g soy protein with 2 mg phytoestrogens, representative of a Western diet) or high-dose phytoestrogen (30 g soy protein with 16 mg phytoestrogens, representative of a vegetarian diet) supplementation for 8 wk, then crossed over after an 8-wk washout period. Main Outcome Measures: The primary outcome was progression to overt hypothyroidism, with secondary outcome measures of blood pressure, insulin resistance, lipids, and highly sensitive C-reactive protein (hsCRP). Results: Six female patients in the study progressed into overt hypothyroidism with a standardized rate ratio of 3.6 (95% confidence interval, 1.9, 6.2) after 16-mg phytoestrogen supplementation. Both systolic and diastolic blood pressure decreased with 16 mg phytoestrogens, whereas systolic pressure alone decreased with 2 mg phytoestrogens. Insulin resistance (homeostasis model assessment of insulin resistance, 3.5 ± 0.09 vs. 2.6 ± 0.08; P < 0.02) and hsCRP (4.9 ± 0.04 vs. 3.9 ± 0.03; P < 0.01) decreased with 16 mg phytoestrogens. Lipid profile remained unchanged. Conclusion: There is a 3-fold increased risk of developing overt hypothyroidism with dietary supplementation of 16 mg soy phytoestrogens with subclinical hypothyroidism. However, 16-mg soy phytoestrogen supplementation significantly reduces the insulin resistance, hsCRP, and blood pressure in these patients. Copyright © 2011 by The Endocrine Society
Long-term effects of allergen sensitization and exposure in adult asthma: a prospective study.
BACKGROUND: : We investigated the effects of sensitization and exposure to common domestic allergens on longitudinal changes in lung function and bronchial hyperresponsiveness. METHODS: : Subjects attended 2 visits that were 4 years apart. Skin prick testing was performed and household dust samples were collected for quantification of mite, dog, and cat allergens at baseline. Measurements of lung function, exhaled nitric oxide, and bronchial hyperresponsiveness were completed at both visits. RESULTS: : Dust samples were collected in 165 of the 200 subjects completing both visits. Mean length of follow-up was 47 months. Bronchial hyperresponsiveness, measured at both visits in 86 subjects, deteriorated in those exposed to high mite allergen levels compared with those not exposed [mean (95% CI) doubling dose change PD20 = -0.44 (-1.07 to 0.19) vs 0.82 (0.27 to 1.36)], but improved in those exposed to high dog allergen levels compared with those not exposed [1.10 (0.33 to 1.86) vs 0.10 (-0.39 to 0.58)]. The associations were significant in the multivariate models. Cat allergen exposure was not associated with any changes in lung function, exhaled nitric oxide, or bronchial hyperresponsiveness. CONCLUSIONS: : In a 4-year prospective cohort of persons with asthma, exposure to high levels of dust mite allergens at baseline was associated with a subsequent increase in bronchial hyperresponsiveness
Being Breathed: from King Lear to clinical medicine
This essay explores the therapeutic possibilities opened up by literature for breathless patients today. Focusing on King Lear, it considers Shakespeare’s suggestion that we do not breathe as isolated agents but are instead ‘breathed’ by those who know and observe us. Breath emerges as fundamental to early modern personhood. Many breathless patients today still experience the inseparability of breath and aliveness, and breathlessness becomes ‘a way of life’ as they adapt their sense of what is possible in order to accommodate their condition. This life belongs not only to sufferers, however, but also to those who care for them. Considering recent clinical research on vicarious dyspnoea alongside King Lear reveals the existential and therapeutic potential of breath’s intimate, under-recognised relationality
Structure and lithium-ion dynamics in fluoride-doped cubic Li7La3Zr2O12 (LLZO) garnet for Li solid-state battery applications
The lithium-stuffed garnet Li7La3Zr2O12 (LLZO), when suitably doped, is a promising candidate material for use as a solid-state electrolyte within advanced Li-ion batteries. It possesses the thermal and mechanical stability of many inorganic ceramics, while exhibiting high Li+ ionic conductivities often associated with conventional liquid electrolytes, making it an ideal component for large-scale energy storage. However, only the high-temperature cubic phase has any meaningful Li-ion conductivity. Typically the formation of this phase is achieved through cation doping (e.g., Al3+ on the Li site) to lower the Li content and so disrupt Li ordering. However, Li-site doping, in particular, may potentially lead to some disruption of the Li-ion conduction pathways and suboptimal ionic conductivities. Consequently, other novel doping strategies involving the anion site are gaining traction, for example, F– for O2– as an alternative strategy to lower the Li content without directly blocking the lithium-diffusion pathways. For the first time, classical potential-based simulations have been employed to simulate the incorporation of fluoride anions into LLZO. Low incorporation energies have been calculated, suggesting fluoride anions are stable on the oxygen sites with a compensating lithium-ion vacancy defect. Molecular dynamics calculations suggest a definitive phase transition to the more desirable cubic phase of LLZO when doped with fluoride at temperature significantly lower than that for the tetragonal–cubic phase transition found for pure LLZO. Remarkably, the lithium-ion transport properties are shown to improve in the fluoride-doped samples particularly at low temperatures due to the stabilization of the cubic phase, suggesting anion doping of garnet systems may be a compelling alternative route to optimize the ionic conductivity
Fate of tetracycline and sulfonamide resistance genes in a grassland soil amended with different organic fertilizers
This study provided an assessment of the environmental fate of antibiotic resistance genes (ARGs) in a Scottish grassland field repeatedly treated with different organic fertilizers. The impacts of manure, biosolids and municipal food-derived compost on the relative abundances of tetracycline ARGs (tetA, tetB, tetC, tetG and tetW), sulfonamide ARGs (sul1 and sul2) and class 1 integron-integrase gene (IntI1) in soils were investigated, with inorganic fertilizer (NPK) as a comparison. The background soil with a history of low intensity farming showed a higher total relative abundance of tet ARGs over sul ARGs, with tetracycline efflux genes occurring in a higher frequency. In all treatments, the relative abundances of most ARGs detected in soils decreased over time, especially IntI1 and tet ARGs. This general attenuation of soil ARGs is a reflection of changes in the soil microbial community, which is supported by the result that almost all the soils at the end of the experiment had different bacterial communities from the untreated soil at the beginning of the experiment. Multiple applications of organic fertilizers to some extent counteracted the decreasing trend of soil ARGs relative abundances, which resulted in higher ARGs relative abundances in comparison to NPK, either by a lesser decrease of IntI1 and tet ARGs or an increase of sul ARGs. The enhancement of existing soil ARG prevalence by organic fertilizers was strongly dependent on the organic fertilizer type and the particular ARG. Compost contained the lowest relative abundance of inherent ARGs and had the least effect on the soil ARG decrease after application. The relative increase of tet ARGs caused by biosolids was larger than that of sul ARGs, while manure caused the opposite effect. Fertilization practices did not exert effective impacts on the soil bacterial community, although it caused significant changes in the profile of the ARG pool. Organic fertilization may thus accelerate the dissemination of ARGs in soil mainly through horizontal gene transfer (HGT), consistent with the enrichment of IntI1 in organic fertilized soils
High-sensitivity cardiac troponin concentrations at presentation in patients with ST-segment elevation myocardial infarction
No abstract available
Matrilysin-dependent Elastolysis by Human Macrophages
Human macrophages found in juxtaposition to fragmented elastin in vivo express the elastolytic matrix metalloproteinases (MMPs) progelatinase B, prometalloelastase, and promatrilysin. Though MMPs can degrade a range of extracellular matrix components, increasing evidence suggests that preferred targets in vivo include nonmatrix substrates such as chemokines and growth factors. Hence, the means by which MMPs participate in elastin turnover remain undefined as does the identity of the elastolysins. Herein, human macrophage cultures have been established that express a complement of elastolytic proteinases similar, if not identical, to that found in vivo. Under plasminogen-free conditions, macrophages preferentially use metalloelastase to mediate elastolysis via a process that deposits active enzyme on elastin surfaces. By contrast, in the presence of plasminogen, human macrophages up-regulate proteolysis 10-fold by processing promatrilysin to an active elastolysin via a urokinase-type plasminogen activator-dependent pathway. Matrilysin-deficient human macrophages fail to mediate an elastolytic response despite the continued expression of gelatinase B and metalloelastase. Thus, acting in concert with cosecreted cysteine proteinases whose activities are constrained to sites of macrophage-elastin contact (Punturieri, A., S. Filippov, E. Allen, I. Caras, R. Murray, V. Reddy, and S.J. Weiss. 2000. J. Exp. Med. 192:789–799), matrilysin confers macrophages with their most potent MMP-dependent elastolytic system
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