181 research outputs found
Thiopeptides Induce Proteasome-Independent Activation of Cellular Mitophagy
Thiopeptide antibiotics are emerging clinical candidates that exhibit potent antibacterial activity against a variety of intracellular pathogens, including Mycobacterium tuberculosis (Mtb). Many thiopeptides directly inhibit bacterial growth by disrupting protein synthesis. However, recent work has shown that one thiopeptide, thiostrepton (TSR), can also induce autophagy in infected macrophages, which has the potential to be exploited for host-directed therapies against intracellular pathogens, such as Mtb. To better define the therapeutic potential of this class of antibiotics, we studied the host-directed effects of a suite of natural thiopeptides that spans five structurally diverse thiopeptide classes, as well as several analogs. We discovered that thiopeptides as a class induce selective autophagic removal of mitochondria, known as mitophagy. This activity is independent of other biological activities, such as proteasome inhibition or antibiotic activity. We also find that many thiopeptides exhibit potent activity against intracellular Mtb in macrophage infection models. However, the thiopeptide-induced mitophagy occurs outside of pathogen-containing autophagosomes and does not appear to contribute to thiopeptide control of intracellular Mtb. These results expand basic understanding of thiopeptide biology and provide key guidance for the development of new thiopeptide antibiotics and host-directed therapeutics
Sustainability assessment of electrokinetic bioremediation compared with alternative remediation options for a petroleum release site
Sustainable management practices can be applied to the remediation of contaminated land to maximise
the economic, environmental and social benefits of the process. The Sustainable Remediation Forum UK
(SuRF-UK) have developed a framework to support the implementation of sustainable practices within
contaminated land management and decision making. This study applies the framework, including
qualitative (Tier 1) and semi-quantitative (Tier 2) sustainability assessments, to a complex site where the
principal contaminant source is unleaded gasoline, giving rise to a dissolved phase BTEX and MTBE
plume. The pathway is groundwater migration through a chalk aquifer and the receptor is a water supply
borehole. A hydraulic containment system (HCS) has been installed to manage the MTBE plume
migration. The options considered to remediate the MTBE source include monitored natural attenuation
(MNA), air sparging/soil vapour extraction (AS/SVE), pump and treat (PT) and electrokinetic-enhanced
bioremediation (EK-BIO). A sustainability indictor set from the SuRF-UK framework, including priority
indicator categories selected during a stakeholder engagement workshop, was used to frame the assessments.
At Tier 1 the options are ranked based on qualitative supporting information, whereas in Tier
2 a multi-criteria analysis is applied. Furthermore, the multi-criteria analysis was refined for scenarios
where photovoltaics (PVs) are included and amendments are excluded from the EK-BIO option. Overall,
the analysis identified AS/SVE and EK-BIO as more sustainable remediation options at this site than either
PT or MNA. The wider implications of this study include: (1) an appraisal of the management decision
from each Tier of the assessment with the aim to highlight areas for time and cost savings for similar
assessments in the future; (2) the observation that EK-BIO performed well against key indicator categories
compared to the other intensive treatments; and (3) introducing methods to improve the sustainability
of the EK-BIO treatment design (such as PVs) did not have a significant effect in this instance
Phenotypic plasticity, seasonal climate and the population biology of Bicyclus butterflies (Satyridae) in Malawi
Wetensch. publicatieFaculteit der Wiskunde en Natuurwetenschappe
The PHENIX Experiment at RHIC
The physics emphases of the PHENIX collaboration and the design and current
status of the PHENIX detector are discussed. The plan of the collaboration for
making the most effective use of the available luminosity in the first years of
RHIC operation is also presented.Comment: 5 pages, 1 figure. Further details of the PHENIX physics program
available at http://www.rhic.bnl.gov/phenix
Conserved oviposition preferences in alpine leaf beetle populations despite host shifts and isolation
Optical Light Curves of Supernovae
Photometry is the most easily acquired information about supernovae. The
light curves constructed from regular imaging provide signatures not only for
the energy input, the radiation escape, the local environment and the
progenitor stars, but also for the intervening dust. They are the main tool for
the use of supernovae as distance indicators through the determination of the
luminosity. The light curve of SN 1987A still is the richest and longest
observed example for a core-collapse supernova. Despite the peculiar nature of
this object, as explosion of a blue supergiant, it displayed all the
characteristics of Type II supernovae. The light curves of Type Ib/c supernovae
are more homogeneous, but still display the signatures of explosions in massive
stars, among them early interaction with their circumstellar material. Wrinkles
in the near-uniform appearance of thermonuclear (Type Ia) supernovae have
emerged during the past decade. Subtle differences have been observed
especially at near-infrared wavelengths. Interestingly, the light curve shapes
appear to correlate with a variety of other characteristics of these
supernovae. The construction of bolometric light curves provides the most
direct link to theoretical predictions and can yield sorely needed constraints
for the models. First steps in this direction have been already made.Comment: To be published in:"Supernovae and Gamma Ray Bursters", Lecture Notes
in Physics (http://link.springer.de/series/lnpp
Management of multidrug resistant Gram-negative bacilli infections in solid organ transplant recipients: SET/GESITRA-SEIMC/REIPI recommendations
Solid organ transplant (SOT) recipients are especially at risk of developing infections by multidrug resistant (MDR) Gram-negative bacilli (GNB), as they are frequently exposed to antibiotics and the healthcare setting, and are regulary subject to invasive procedures. Nevertheless, no recommendations concerning prevention and treatment are available. A panel of experts revised the available evidence; this document summarizes their recommendations: (1) it is important to characterize the isolateÂŽs phenotypic and genotypic resistance profile; (2) overall, donor colonization should not constitute a contraindication to transplantation, although active infected kidney and lung grafts should be avoided; (3) recipient colonization is associated with an increased risk of infection, but is not a contraindication to transplantation; (4) different surgical prophylaxis regimens are not recommended for patients colonized with carbapenem-resistant GNB; (5) timely detection of carriers, contact isolation precautions, hand hygiene compliance and antibiotic control policies are important preventive measures; (6) there is not sufficient data to recommend intestinal decolonization; (7) colonized lung transplant recipients could benefit from prophylactic inhaled antibiotics, specially for Pseudomonas aeruginosa; (8) colonized SOT recipients should receive an empirical treatment which includes active antibiotics, and directed therapy should be adjusted according to susceptibility study results and the severity of the infection.J.T.S. holds a research contract from the FundaciĂłn para la FormaciĂłn e InvestigaciĂłn de los Profesionales de la Salud de Extremadura (FundeSalud), Instituto de Salud Carlos III. M.F.R. holds a clinical research contract âJuan RodĂ©sâ (JR14/00036) from the Spanish Ministry of Economy and Competitiveness, Instituto de Salud Carlos III
Influence of socioeconomic factors on pregnancy outcome in women with structural heart disease
OBJECTIVE: Cardiac disease is the leading cause of indirect maternal mortality. The aim of this study was to analyse to what extent socioeconomic factors influence the outcome of pregnancy in women with heart disease. METHODS: The Registry of Pregnancy and Cardiac disease is a global prospective registry. For this analysis, countries that enrolled â„10 patients were included. A combined cardiac endpoint included maternal cardiac death, arrhythmia requiring treatment, heart failure, thromboembolic event, aortic dissection, endocarditis, acute coronary syndrome, hospitalisation for cardiac reason or intervention. Associations between patient characteristics, country characteristics (income inequality expressed as Gini coefficient, health expenditure, schooling, gross domestic product, birth rate and hospital beds) and cardiac endpoints were checked in a three-level model (patient-centre-country). RESULTS: A total of 30 countries enrolled 2924 patients from 89 centres. At least one endpoint occurred in 645 women (22.1%). Maternal age, New York Heart Association classification and modified WHO risk classification were associated with the combined endpoint and explained 37% of variance in outcome. Gini coefficient and country-specific birth rate explained an additional 4%. There were large differences between the individual countries, but the need for multilevel modelling to account for these differences disappeared after adjustment for patient characteristics, Gini and country-specific birth rate. CONCLUSION: While there are definite interregional differences in pregnancy outcome in women with cardiac disease, these differences seem to be mainly driven by individual patient characteristics. Adjustment for country characteristics refined the results to a limited extent, but maternal condition seems to be the main determinant of outcome
New insights into the genetic etiology of Alzheimer's disease and related dementias
Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE Δ4 allele
Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.
BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362
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