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A dynamic metric for near-Earth object (NEO) hazard mitigation quantifies threats from potential NEO impacts with Earth in terms of energy required to perturb threatening NEO orbits to avoid collision. The required energy is based on NEO mass, anticipated velocity change to avoid collision, and the momentum coupling coefficient.
Hyperoxic lung injury may be mitigated by increasing alveolar epithelial antioxidant activity. We examined whether intratracheal instillation of superoxide dismutase (SOD) and catalase, conjugated to polyethylene glycol (PEG) to permit cellular access, reduces hyperoxic lung injury. Adult rats, pretreated intratracheally with 1,500 U PEG-SOD and 10,000 U PEG-catalase or with inactivated PEG-SOD/catalase, 1% PEG, or saline (treated controls), were exposed to hyperoxia (fraction of inspired oxygen > 0.95) for 48 h and compared with untreated air controls. Alveolar wash protein values in the treated control groups were significantly higher than in the PEG-SOD/catalase and air control groups, which had comparable values. Lung homogenate and alveolar type II cell SOD and catalase activities were higher after PEG-SOD/catalase treatment and lower after the control treatments when compared with untreated air controls. Lung homogenate dipalmitoyl phosphatidylcholine decreased and alveolar wash dipalmitoyl phosphatidylcholine increased after hyperoxia, but these changes were less after PEG-SOD/catalase treatment. Rats pretreated intratracheally with PEG-SOD/catalase survived significantly longer in hyperoxia than saline controls. These data indicate the potential of intratracheal antioxidant treatment to reduce pulmonary oxygen toxicity.
In the corpulent James C. Russell corpulent (JCR:LA-cp) rat, hyperinsulinemia leads to induction of lipogenic enzymes via enhanced expression of sterol-regulatory-binding protein (SREBP)-1c. This results in increased hepatic lipid production and hypertriglyceridemia. Information regarding down-regulation of SREBP-1c and lipogenic enzymes by dietary fatty acids in this model is limited. We therefore assessed de novo hepatic lipogenesis and hepatic and plasma lipids in corpulent JCR rats fed diets enriched in olive oil or menhaden oil. Using microarray and Northern analysis, we determined the effect of these diets on expression of mRNA for lipogenic enzymes and other proteins related to lipid metabolism. In corpulent JCR:LA-cp rats, both the olive oil and menhaden oil diets reduced expression of SREBP-1c, with concomitant reductions in hepatic triglyceride content, lipogenesis, and expression of enzymes related to lipid synthesis. Unexpectedly, expression of many peroxisomal proliferator-activated receptor-dependent enzymes mediating fatty acid oxidation was increased in livers of corpulent JCR rats. The menhaden oil diet further increased expression of these enzymes. Induction of SREBP-1c by insulin is dependent on liver x receptor (LXR)alpha. Although hepatic expression of mRNA for LXR itself was not increased in corpulent rats, expression of Cyp7a1, an LXR-responsive gene, was increased, suggesting increased LXR activity. Expression of mRNA encoding fatty acid translocase and ATP-binding cassette subfamily DALD member 3 was also increased in livers of corpulent JCR rats, indicating a potential role for these fatty acid transporters in the pathogenesis of disordered lipid metabolism in obesity. This study clearly demonstrates that substitution of dietary polyunsaturated fatty acid for carbohydrate in the corpulent JCR:LA-cp rat reduces de novo lipogenesis, at least in part, by reducing hepatic expression of SREBP-1c and that strategies directed toward reducing SREBP-1c expression in the liver may mitigate the adverse effects of hyperinsulinemia on hepatic lipid production.
BACKGROUND: Although prophylactic IV administration of lidocaine attenuates the response to a variety of inhalation challenges, its effect on airway resistance after endotracheal intubation in patients with asthma is unclear. We tested the hypothesis that IV lidocaine attenuates intubation-evoked bronchoconstriction in patients with asthma. METHODS: Thirty patients with asthma (age 49.1 +/- 15.6 yr [mean +/- sd]) undergoing intubation after standardized anesthetic induction (etomidate 0.3 mg/kg, fentanyl 5 microg/kg, rocuronium 0.6 mg/kg, 50% nitrous oxide) were studied. Airway resistance was measured immediately after intubation and 5, 10, and 15 min later. Five minutes after intubation, either lidocaine (2 mg/kg IV for 5 min, followed by 3 mg x kg(-1) x h(-1) for 10 min) or saline was administered. RESULTS: Airway resistance immediately after intubation averaged 23 +/- 12 cm H2O x s x L(-1). Airway resistance further increased (+38%) after administration of saline, but decreased (-26%, P < 0.004) to less than the initial values after lidocaine. CONCLUSIONS: IV lidocaine given after endotracheal intubation mitigates bronchoconstriction in patients with asthma.
BACKGROUND: Hyperexcitability of N-methyl-D-aspartate (NMDA) receptors may play a role in the persistence of phantom pain. Dextromethorphan (DM) blocks NMDA receptors. METHODS: Eight cancer and two noncancer amputees with established, disabling phantom pain received oral DM 60 or 90 mg twice daily (BID) in a three-period double-blind crossover placebo-controlled trial. This followed an open-phase trial in which either dose was given three times daily if pain relief during the double-blind phase was <50% of pretreatment intensity. Patients then underwent a 3-month phase of treatment with the best regimen and a subsequent 1-month posttreatment follow-up. RESULTS: All patients reported a >50% decrease in pain intensity, better mood, and lower sedation in each treatment phase. Four individuals reported this level of pain relief with the 60-mg and one with the 90-mg BID regimen during the double-blind phase, whereas two amputees benefited from the 60-mg and three from the 90-mg thrice-daily regimen in the open-phase trial. One reported exacerbation of pain with the 90-mg BID regimen, and three reported pain rebound at the 1-month posttreatment follow-up phase. Three patients stopped all previous analgesic use during the study. CONCLUSIONS: Persistent phantom pain probably involves NMDA receptor hyperexcitability because DM 120 to 270 mg/day mitigated the pain satisfactorily.
Social scientific work on the suppression, mitigation or denial of prejudiced attitudes has tended to focus on the strategic self-presentation and self-monitoring undertaken by individual social actors on their own behalf. In this paper, we argue that existing perspectives might usefully be extended to incorporate three additional considerations. First, that social actors may, on some occasions, act to defend not only themselves, but also others from charges of prejudice. Second, that over the course of any social encounter, interactants may take joint responsibility for policing conversation and for correcting and suppressing the articulation of prejudiced talk. Third, that a focus on the dialogic character of conversation affords an appreciation of the ways in which the status of any particular utterance, action or event as 'racist' or 'prejudiced' may constitute a social accomplishment. Finally, we note the logical corollary of these observations - that in everyday life, the occurrence of 'racist discourse' is likely to represent a collaborative accomplishment, the responsibility for which is shared jointly between the person of the speaker and those other co-present individuals who occasion, reinforce or simply fail to suppress it.
We investigate the extreme-ultraviolet (EUV) emission from targets that contain tin as an impurity and the advantages of using these targets for ion debris mitigation by use of a magnetic field. The EUV spectral features were characterized by a transmission grating spectrograph. The in-band EUV emission energy was measured with a calorimeter of absolute calibration. The ion flux coming from the plume was measured with a Faraday cup. Our studies indicate that 0.5% Sn density is necessary to obtain a conversion efficiency very close to that of full-density Sn. The use of Sn-doped low-Z targets provides a narrower unresolved transition array and facilitates better control of energetic ions in the presence of a moderate magnetic field of 0.64 T.
To assess the ability of the heat-inducible molecular chaperone heat-shock protein 70 (Hsp70) to mitigate a specific developmental lesion, we administered the antimicrotubule drugs vinblastine (VB) and colchicine (COL) to larvae of Drosophila engineered to express differing levels of Hsp70 after heat pretreatment (HP). VB and COL decreased survival during metamorphosis, disrupted development of the adult eye and other structures as well as their precursor imaginal disks, and induced chromosome nondisjunction in the wing imaginal disk as indicated by the somatic mutation and recombination test (SMART) assay. Hsp70-inducing HP reduced many of these effects. For the traits viability, adult eye morphology, eye imaginal disk morphology, cell death in the eye imaginal disks, and single and total mutant clone formation in the SMART assay, HP reduced the impact of VB to a greater extent in Drosophila with 6 hsp70 transgenes than in a sister strain from which the transgenes had been excised. Because the extra-copy strain has higher levels of Hsp70 than does the excision strain but is otherwise almost identical in genetic background to the excision strain, these outcomes are attributable to Hsp70. The hsp70 copy number had a variable interaction with HP and COL administration.
INTRODUCTION: Comorbidities between mental disorders and irritable bowel syndrome (IBS) have been widely reported, yet associations between mental wellbeing and IBS, particularly regarding underlying genetic modification and proteomic signatures, remain underexplored. METHODS: This prospective cohort study analyzed 75,842 IBS-free participants aiming to investigate the prospective association between mental wellbeing and the risk of IBS in UK Biobank. Mental wellbeing was assessed through life satisfaction, positive affect, neuroticism, and depressive/anxiety symptoms. Cox models evaluate the hazard ratio (HR) for mental wellbeing and plasma proteome in relation to incident IBS during follow-up. Proteomic profiling identified mental wellbeing-associated proteins, with pathway enrichment analysis revealing biological mechanisms. Mediation and Mendelian randomization analyses further examine intermediate pathways and causality. RESULTS: With a 12.4-year follow-up period, 1,400 cases of incident IBS were documented. Better mental wellbeing mitigated IBS risk dose-dependently (low risk group: HR, 0.37; 95% confidence interval [CI]: 0.31-0.43). Higher life satisfaction (HR, 0.41; 95% CI: 0.30-0.56) and positive affect (HR, 0.50; 95% CI: 0.41-0.62) were inversely associated with IBS risk, whereas neuroticism (HR, 2.35; 95% CI: 1.92-2.88) and depressive/anxiety symptoms (HR, 3.09; 95% CI: 2.17-4.42) increased the risk. Findings remained consistent in across prevalent IBS and IBS subtypes. Mental wellbeing effects were independent of genetic predisposition. Mediation analyses revealed about 27% of protective effect of mental wellbeing were mediated through reduced depression and anxiety. Mendelian randomization supports causal protective effects of positive mental wellbeing on IBS. Proteomic profiling identified mental wellbeing-associated proteins mainly enriched in cytokine-cytokine receptor interactions. Chromogranin A and gastrin emerged as key protein biomarkers, showing significant associations with both mental wellbeing components and IBS risk. DISCUSSION: Our study demonstrates that enhanced mental wellbeing confers substantial protection against IBS development, highlighting psychological interventions as potential primary prevention strategies.
OBJECTIVES: The purpose of this paper is to provide smokers with information on the relative benefits of mitigating radon and quitting smoking in reducing radon-related lung cancer risk. METHODS: The standard radon risk model, linked with models characterizing residential radon exposure and patterns of moving to new homes, was used to estimate the risk reduction produced by remediating high-radon homes, quitting smoking, or both. RESULTS: Quitting smoking reduces lung cancer risk from radon more than does reduction of radon exposure itself. CONCLUSIONS: Smokers should understand that, in addition to producing other health benefits, quitting smoking dominates strategies to deal with the problem posed by radon.
Young to middle-aged residents of impoverished urban areas suffer extra-ordinary rates of excess mortality, to which deaths from chronic disease contribute heavily. Understanding of urban health disadvantages and attempts to reverse them will be incomplete if the structural factors that produced modern minority ghettos in central cities are not taken into account. Dynamic conceptions of the role of race/ethnicity in producing health inequalities must encompass (1) social relationship between majority and minority populations that privilege the majority population and (2) the autonomous institutions within minority populations that members develop and sustain to mitigate, resist, or undo the adverse effects of discrimination. Broad social and economic policies that intensify poverty or undermine autonomous protections can reap dire consequences for health. Following from this structural analysis and previous research, guiding principles for action and suggestions for continued research are proposed. Without taking poverty and race/ethnicity into account, public health professionals who hope to redress the health problems of urban life risk exaggerating the returns that can be expected of public health campaigns or overlooking important approaches for mounting successful interventions.
Cognitive, perceptual, and motor deficits are part of the constellation of symptoms found in various hypoglycemic conditions. Since neurogenic symptoms and altered states of consciousness affect driving skills, hypoglycemia should be considered a mitigating factor in vehicular accidents.
The objective of this study was to determine whether feeding a vitamin E-rich diet would benefit nursery pigs infected with porcine reproductive and respiratory syndrome virus (PRRSV). Sixty-four pigs were subjected to one of four treatment combinations (2 x 2 factorial) of dietary vitamin E (adequate or excess) and PRRSV (medium or inoculation with VR-2385 isolate P-129). Pigs were fed experimental diets during a 3-wk period before inoculation as well as during a 12-d period after inoculation. Growth performance was determined throughout the study, and lipid peroxidation in liver, glutathione peroxidase (GPX) activity in serum, circulating white blood cells, and serum interleukin-1beta (IL-1beta) and interferon-gamma (IFN-gamma) were determined in samples collected from pigs killed 4 or 12 d after inoculation. Infection by PRRSV (P < 0.001) induced a marked decrease in both ADFI and ADG, but neither the main effect of diet nor the diet x PRRSV interaction was significant. Neither diet nor PRRSV affected feed efficiency. At 12 d after inoculation, lipid peroxidation in liver and GPX activity in serum were lower in pigs fed excess vitamin E than in those fed adequate vitamin E (P < 0.01), suggesting that the diet high in vitamin E bolstered the antioxidant status of the pigs. However, PRRSV did not affect lipid peroxidation in liver or serum GPX activity, and the diet x PRRSV interaction was not significant. White blood cell counts were decreased and IFN-gamma, and IL-1beta were increased (P < 0.05) 4 and 12 d after inoculation in PRRSV-infected pigs, but neither diet nor the diet x PRRSV interaction was significant. Collectively, these results indicate that increasing antioxidant defenses by feeding high levels of vitamin E did not ameliorate the effects of PRRSV on decreased growth, leukopenia, and increased serum IL-1beta and IFN-gamma. Thus, feeding nursery pigs a diet high in vitamin E may not be useful for mitigating the acute morbidity effects of PRRSV infection.
Use of ionophores in cattle diets has been proposed as a strategy for mitigation of enteric CH4 emissions. Short- and long-term effects of feeding a single ionophore (monensin) or rotation of 2 ionophores (monensin and lasalocid) on enteric CH4 emissions were evaluated in 36 Angus yearling steers (328 +/- 24.9 kg of BW) over a 16-wk period. Steers were randomly assigned to 6 dietary treatments of 6 steers each. The 6 diets were low-concentrate without ionophore supplementation, low-concentrate with monensin supplementation, low-concentrate with a 2-wk rotation of monensin and lasalocid supplementation, high-concentrate without ionophore supplementation, high-concentrate with monensin supplementation, and high-concentrate with a 2-wk rotation of monensin and lasalocid supplementation. Daily enteric CH4 emissions, as measured using the SF(6) tracer gas technique, ranged from 54.7 to 369.3 L/steer daily. Supplementing ionophores decreased (P < 0.05) enteric CH4 emissions, expressed as liters per kilogram of DMI or percentage of GE intake, by 30% for the first 2 wk and by 27% for the first 4 wk, for cattle receiving the high-concentrate and low-concentrate diets, respectively. Cattle fed a rotation of ionophores did not (P > 0.05) exhibit a greater decrease and did not (P > 0.05) have a longer period of depressed enteric CH4 emissions compared with cattle receiving monensin only. Ionophore supplementation did not (P > 0.05) alter total ruminal fluid VFA concentration; however, the acetate:propionate ratio and ammonia-N concentration in ruminal fluid were decreased (P < 0.001) from the time that ionophores were introduced to the time they were removed from the diets. Both monensin and the rotation of monensin and lasalocid decreased (P < 0.001) total ciliate protozoal populations by 82.5% in the first 2 wk and by 76.8% in the first 4 wk during which they were supplemented in the high-concentrate and low-concentrate diets, respectively. Original ciliate protozoal populations were restored by the fourth and sixth week of supplementation when cattle were fed the high- or low-concentrate diets, respectively. No significant change was observed thereafter. These data suggest that the effects of ionophores on enteric CH(4) production are related to ciliate protozoal populations and that ciliate protozoal populations can adapt to the ionophores present in either low- or high-concentrate diets. Rotation of monensin and lasalocid did not (P > 0.05) prevent ciliate protozoal adaptation to ionophores.
Half of the mice in both the monosodium-L-glutamate (MSG)-induced obesity and saline control groups were given BRL 26830A via a gastric tube at a daily dose of 5 mg/kg for 2 weeks, and the other half given distilled water. BRL 26830A administration significantly increased guanosine-5'-diphosphate (GDP)-binding in brown adipose tissue (BAT) and the resting metabolic rate (RMR), and significantly reduced retroperitoneal white adipose tissue (WAT) pads in both groups. It also markedly reduced body weight in MSG obese mice that had reduced BAT thermogenesis and decreased RMR. However, food intake was unchanged in both groups. Neither beta 1- nor beta 2-selective antagonists affected the increase of RMR induced by BRL 26830A, but a non-selective beta-antagonist completely inhibited its increase. These results suggest that BRL 26830A, which is a new beta-adrenoceptor agonist, stimulates BAT thermogenesis, increases RMR, and reduces WAT, thus contributing to the mitigation of obesity.
Two experiments were conducted to determine whether supplemental levels of L-proline in the diets of broiler chickens would mitigate the skin weakening effect caused by continuous feeding of the anticoccidial halofuginone. In Experiment 1, tensile strength and collagen levels in thigh apteria skin were determined at 21 and 42 d of age in male broilers fed 0, .5, and 1% L-proline with either halofuginone (3 mg/kg) or salinomycin (61 mg/kg). In Experiment 2, the same measurements were made on female broilers receiving diets containing halofuginone and supplemented with 0, .5, or 1% L-proline, 1% L-proline through 21 d of age, or 1% L-glutamic acid through 21 d of age, or a diet containing high L-proline feedstuffs (corn gluten meal and ring dried blood meal). In Experiment 1, dermis thickness of thigh apteria was measured in the males at Day 21. Skin strength was increased in male and female broilers fed halofuginone with addition of .5 and 1% L-proline, respectively, at 21 and 42 d of age. Continuous incorporation of synthetic L-proline into diets was shown to improve skin strength in females, whereas diets formulated to contain high levels of L-proline from feedstuffs, 21-d feeding of L-proline, or L-glutamic acid did not increase skin strength.
Immunogenicity of CRISPR-associated nucleases (Cas) is a critical barrier to the development of safe and effective genome editing therapies. These proteins inherently pose a risk of immune recognition due to their prokaryotic origins. A multitude of factors, such as the delivery vehicle, the route of administration, components of the therapeutics, tissue microenvironment, and pre-existing immunity, also contribute to the complexity of the host immune response to Cas proteins. As CRISPR-based therapies advance into clinical settings, it is imperative to elucidate and address the immunogenicity of Cas proteins. Here, using Cas9 as an example, we review the current understanding of Cas protein immunogenicity, the challenges it poses for therapeutic application, and strategies to mitigate cellular immune responses to Cas proteins.
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