RNA has the intrinsic property to base pair, forming complex structures fundamental to its diverse functions. Here, we develop PARIS, a method based on reversible psoralen crosslinking for global ...mapping of RNA duplexes with near base-pair resolution in living cells. PARIS analysis in three human and mouse cell types reveals frequent long-range structures, higher-order architectures, and RNA-RNA interactions in trans across the transcriptome. PARIS determines base-pairing interactions on an individual-molecule level, revealing pervasive alternative conformations. We used PARIS-determined helices to guide phylogenetic analysis of RNA structures and discovered conserved long-range and alternative structures. XIST, a long noncoding RNA (lncRNA) essential for X chromosome inactivation, folds into evolutionarily conserved RNA structural domains that span many kilobases. XIST A-repeat forms complex inter-repeat duplexes that nucleate higher-order assembly of the key epigenetic silencing protein SPEN. PARIS is a generally applicable and versatile method that provides novel insights into the RNA structurome and interactome.
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•PARIS yields in vivo RNA duplex maps of human and mouse cells.•In vivo maps discover extensive long-range and alternative RNA structures.•PARIS guides evolution analysis and validation of duplex function.•Unique duplex fold of XIST A-repeat nucleates XIST-SPEN lncRNP.
A method for global mapping of RNA duplexes in living cells with near base-pair resolution, called PARIS, reveals extensive long-range structures, higher-order architectures, alternative structures, and RNA-RNA interactions across the transcriptome and uncovers a unique architecture of Xist and its specific interaction with a key silencing factor.
Iron is essential for nearly all bacterial pathogens, including Mycobacterium tuberculosis (Mtb), but is severely limited in the human host. To meet its iron needs, Mtb secretes siderophores, small ...molecules with high affinity for iron, and takes up iron-loaded mycobactins (MBT) and carboxymycobactins (cMBT), from the environment. Mtb is also capable of utilizing heme and hemoglobin which contain more than 70% of the iron in the human body. However, many components of these iron acquisition pathways are still unknown. In this study, a high-density transposon mutagenesis coupled with deep sequencing (TnSeq) showed that Mtb exhibits nearly opposite requirements for 165 genes in the presence of heme and hemoglobin versus MBT and cMBT as iron sources. The ESX-3 secretion system was assessed as essential for siderophore-mediated iron uptake and, surprisingly, also for heme utilization by Mtb. Predictions derived from the TnSeq analysis were validated by growth experiments with isogenic Mtb mutants. These results showed that (i) the efflux pump MmpL5 plays a dominant role in siderophore secretion, (ii) the Rv2047c protein is essential for growth of Mtb in the presence of mycobactin, and (iii) the transcriptional repressor Zur is required for heme utilization by Mtb. The novel genetic determinants of iron utilization revealed in this study will stimulate further experiments in this important area of Mtb physiology.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Tuberculosis poses a global health emergency, which has been compounded by the emergence of drug-resistant Mycobacterium tuberculosis (Mtb) strains. We used whole-genome sequencing to compare the ...accumulation of mutations in Mtb isolated from cynomolgus macaques with active, latent or reactivated disease. We sequenced 33 Mtb isolates from nine macaques with an average genome coverage of 93% and an average read depth of 117×. Based on the distribution of SNPs observed, we calculated the mutation rates for these disease states. We found a similar mutation rate during latency as during active disease or in a logarithmically growing culture over the same period of time. The pattern of polymorphisms suggests that the mutational burden in vivo is because of oxidative DNA damage. We show that Mtb continues to acquire mutations during disease latency, which may explain why isoniazid monotherapy for latent tuberculosis is a risk factor for the emergence of isoniazid resistance.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Jean-Paul Sartre (1905–1980) was one of the most influential thinkers of the twentieth century. Regarded as the father of existentialist philosophy, he was also a political critic, moralist, ...playwright, novelist, and author of biographies and short stories. Thomas R. Flynn provides the first book-length account of Sartre as a philosopher of the imaginary, mapping the intellectual development of his ideas throughout his life, and building a narrative that is not only philosophical but also attentive to the political and literary dimensions of his work. Exploring Sartre's existentialism, politics, ethics, and ontology, this book illuminates the defining ideas of Sartre's oeuvre: the literary and the philosophical, the imaginary and the conceptual, his descriptive phenomenology and his phenomenological concept of intentionality, and his conjunction of ethics and politics with an 'egoless' consciousness. It will appeal to all who are interested in Sartre's philosophy and its relation to his life.
Abstract Purpose To evaluate the safety and intraocular pressure (IOP)-lowering effect of a biodegradable bimatoprost sustained-release implant (Bimatoprost SR). Design Phase I/II, prospective, ...24-month, dose-ranging, paired-eye controlled clinical trial. Methods At baseline following washout, open-angle glaucoma patients (n=75) were administered Bimatoprost SR (6-μg, 10-μg, 15-μg, or 20-μg) intracamerally in the study eye; the fellow eye began topical bimatoprost 0.03% QD. Rescue topical IOP-lowering medication or a single repeat treatment with implant was allowed. The primary endpoint was IOP change from baseline. The main safety measure was adverse events. Results through month 6 are reported. Results Bimatoprost SR provided rapid, sustained IOP lowering. Overall mean IOP reduction from baseline through week 16 in study eyes was 7.2, 7.4, 8.1, and 9.5 mm Hg with the 6-μg, 10-μg, 15-μg, and 20-μg dose strengths of implant, respectively, versus 8.4 mm Hg in topical bimatoprost-treated pooled fellow eyes (data censored at rescue/retreatment). Rescue/retreatment was not required in 91% and 71% of study eyes up to week 16 and month 6, respectively. Adverse events in study eyes usually occurred within 2 days after the injection procedure and were transient. Conjunctival hyperemia with onset later than 2 days after the injection procedure was more common with topical bimatoprost than Bimatoprost SR (17.3% vs. 6.7% of eyes). Conclusions Bimatoprost SR demonstrated favorable efficacy and safety through 6 months. All dose strengths were comparable to topical bimatoprost in overall IOP reduction through week 16. A single administration controlled IOP in the majority of patients for up to 6 months.
It is unclear whether certain bacteria initiate the development of inflammatory jaw conditions, or whether these diseases create a milieu for dysbiosis and secondary colonization of indigenous flora. ...At present, there are no comparative studies on the types of bacteria that colonize different inflammatory jaw conditions. Accordingly, this study aims to identify and compare the types of bacteria isolated in osteomyelitis, osteoradionecrosis, and MRONJ.
This is a retrospective cohort study of patients diagnosed with inflammatory jaw conditions. The predictor variables were classification of bacteria as oral flora, categorized herein as resident bacteria, non-resident bacteria, or opportunistic organisms. The outcome variables were a diagnosis of osteomyelitis, osteoradionecrosis, and MRONJ. Covariates were age, sex, penicillin allergy, a diagnosis of diabetes and a history of smoking. Data analysis was performed using ANOVA and chi-squared tests.
A total of 105 patients with inflammatory jaw conditions were enrolled. The final sample size was 69 subjects of which 16 were diagnosed with osteomyelitis, 20 with osteoradionecrosis, and 33 with MRONJ. There was no difference in the frequency that resident bacteria were isolated. Non-resident bacteria, which included Staphylococcus and Enterococcus among others, were isolated more frequently at 75% in osteomyelitis compared to 60% in osteoradionecrosis and 48% in MRONJ cases. There is weak evidence of significant difference when comparing osteomyelitis and MRONJ cases (P = .08). Opportunistic organisms, which included Mycobacterium and Candida, were isolated more frequently in osteoradionecrosis at 30% compared to 12.5% in osteomyelitis and 12.12% in MRONJ cases. There is weak evidence of significant difference when comparing osteoradionecrosis and MRONJ cases (P = .1).
Non-resident bacteria including Staphylococcus and Enterococcus may be more frequently isolated in patients with osteomyelitis, while opportunistic organisms like Mycobacterium and Candida may be more frequently found in patients diagnosed with osteoradionecrosis.
Patients with newly diagnosed, advanced-stage, follicular grade 1 non-Hodgkin's lymphoma (NHL) are often asymptomatic and can be observed without immediate chemotherapy. The goals of this study were ...to assess the overall response rate (ORR) to rituximab in this patient population and to determine the time-to-progression (TTP) and time-to-subsequent-chemotherapy (TTSC).
Eligible patients had untreated follicular grade 1 NHL, and measurable stage III/IV disease. Patients received rituximab 375 mg/m(2) intravenous weekly x 4 doses and were then followed for response and progression; no maintenance therapy was provided.
Thirty-seven patients were accrued; one patient was ineligible. The median age was 59 years (range, 29 to 83 years). Six patients (18%) had elevated lactate dehydrogenase levels. The ORR was 72%, with 36% complete remissions. Fourteen (39%) of 36 patients remain in unmaintained remission, two died without disease progression, and three died with disease progression. Twenty (56%) of 36 patients have disease progression. The median TTP was 2.2 years (95% CI, 1.3 to not yet reached). Eighteen patients have subsequently been treated with chemotherapy, with a median TTSC of 2.3 years (95% CI, 1.6 to not yet reached). Patients with a high lactate dehydrogenase level had a lower ORR of 33% and a short TTP of only 6 months.
Rituximab can be safely administered to patients with advanced-stage follicular grade 1 NHL with efficacy and minimal toxicity. This therapy is highly active and offers an acceptable alternative to observation in this patient population. Patients with high LDH should not be considered for rituximab monotherapy.
•A survey was conducted on the training experiences of immigrant construction workers.•Results were grouped by business size (50 or fewer workers or more than 50 workers).•There were deficits in the ...amount, frequency, and type of training in smaller firms.•Results show the need for a targeted approach to training this vulnerable population.
Collaborative efforts between the National Institute for Occupational Safety and Health (NIOSH) and the American Society of Safety Engineers (ASSE) led to a report focusing on overlapping occupational vulnerabilities, specifically small construction businesses employing young, non-native workers. Following the report, an online survey was conducted by ASSE with construction business representatives focusing on training experiences of non-native workers. Results were grouped by business size (50 or fewer employees or more than 50 employees). Smaller businesses were less likely to employ a supervisor who speaks the same language as immigrant workers (p < .001). Non-native workers in small businesses received fewer hours of both initial safety training (p = .005) and monthly ongoing safety training (p = .042). Immigrant workers in smaller businesses were less likely to receive every type of safety training identified in the survey (including pre-work safety orientation p < .001, job-specific training p < .001, OSHA 10-hour training p = .001, and federal/state required training p < .001). The results highlight some of the challenges a vulnerable worker population faces in a small business, and can be used to better focus intervention efforts. Among businesses represented in this sample, there are deficits in the amount, frequency, and format of workplace safety and health training provided to non-native workers in smaller construction businesses compared to those in larger businesses. The types of training conducted for non-native workers in small business were less likely to take into account the language and literacy issues faced by these workers. The findings suggest the need for a targeted approach in providing occupational safety and health training to non-native workers employed by smaller construction businesses.
Background
Construction is a dangerous industry with a large number of small businesses. Because they require minimal resources to deliver, toolbox talks may be an ideal training format for small ...construction contractors.
Methods
Eight toolbox talks were developed, each with two versions. One version of each toolbox talk was standard and one version included a narrative and discussion questions. Participants were randomly assigned to receive the standard or the narrative version. Pre‐ and post‐intervention surveys measured demographics, workplace safety climate, and knowledge. The post‐intervention survey also measured training impact.
Results
Including narratives with discussion questions significantly increased knowledge gain and led to increased training impact. Less experienced workers were more likely to gain knowledge and training impact compared to more experienced workers. There were no significant changes in workplace safety climate.
Conclusions
The results suggest that including a narrative and discussion questions increases toolbox talk effectiveness.
Flynn et al. Respond Flynn, Michael A; Cunningham, Thomas R; Ahonen, Emily Q ...
American journal of public health (1971),
09/2018, Letnik:
108, Številka:
9
Journal Article
PDF
