The transcriptional repressor protein NsrR senses nitric oxide directly via a [2Fe-2S] cluster

The regulatory protein NsrR, a member of the Rrf2 family of transcription repressors, is specifically dedicated to sensing nitric oxide (NO) in a variety of pathogenic and non-pathogenic bacteria. It has been proposed that NO directly modulates NsrR activity by interacting with a predicted [Fe-S] cluster in the NsrR protein, but no experimental evidence has been published to support this hypothesis. Here we report the purification of NsrR from the obligate aerobe Streptomyces coelicolor. We demonstrate using UV-visible, near UV CD and EPR spectroscopy that the protein contains an NO-sensitive [2Fe-2S] cluster when purified from E. coli. Upon exposure of NsrR to NO, the cluster is nitrosylated, which results in the loss of DNA binding activity as detected by bandshift assays. Removal of the [2Fe-2S] cluster to generate apo-NsrR also resulted in loss of DNA binding activity. This is the first demonstration that NsrR contains an NO-sensitive [2Fe-2S] cluster that is required for DNA binding activity

9-Genes Reinforce the Phylogeny of Holometabola and Yield Alternate Views on the Phylogenetic Placement of Strepsiptera

Background: The extraordinary morphology, reproductive and developmental biology, and behavioral ecology of twisted wing parasites (order Strepsiptera) have puzzled biologists for centuries. Even today, the phylogenetic position of these enigmatic “insects from outer space” [1] remains uncertain and contentious. Recent authors have argued for the placement of Strepsiptera within or as a close relative of beetles (order Coleoptera), as sister group of flies (order Diptera), or even outside of Holometabola.Methodology/Principal Findings Here, we combine data from several recent studies with new data (for a total of 9 nuclear genes and ∼13 kb of aligned data for 34 taxa), to help clarify the phylogenetic placement of Strepsiptera. Our results unequivocally support the monophyly of Neuropteroidea ( = Neuropterida + Coleoptera) + Strepsiptera, but recover Strepsiptera either derived from within polyphagan beetles (order Coleoptera), or in a position sister to Neuropterida. All other supra-ordinal- and ordinal-level relationships recovered with strong nodal support were consistent with most other recent studies. Conclusions/Significance: These results, coupled with the recent proposed placement of Strepsiptera sister to Coleoptera, suggest that while the phylogenetic neighborhood of Strepsiptera has been identified, unequivocal placement to a specific branch within Neuropteroidea will require additional study.Organismic and Evolutionary Biolog

The effect of tightly-bound water molecules on scaffold diversity in computer-aided de novo ligand design of CDK2 inhibitors

We have determined the effects that tightly bound water molecules have on the de novo design of cyclin-dependent kinase-2 (CDK2) ligands. In particular, we have analyzed the impact of a specific structural water molecule on the chemical diversity and binding mode of ligands generated through a de novo structure-based ligand generation method in the binding site of CDK2. The tightly bound water molecule modifies the size and shape of the binding site and we have found that it also imposed constraints on the observed binding modes of the generated ligands. This in turn had the indirect effect of reducing the chemical diversity of the underlying molecular scaffolds that were able to bind to the enzyme satisfactorily

Spatio-temporal Models of Lymphangiogenesis in Wound Healing

Several studies suggest that one possible cause of impaired wound healing is failed or insufficient lymphangiogenesis, that is the formation of new lymphatic capillaries. Although many mathematical models have been developed to describe the formation of blood capillaries (angiogenesis), very few have been proposed for the regeneration of the lymphatic network. Lymphangiogenesis is a markedly different process from angiogenesis, occurring at different times and in response to different chemical stimuli. Two main hypotheses have been proposed: 1) lymphatic capillaries sprout from existing interrupted ones at the edge of the wound in analogy to the blood angiogenesis case; 2) lymphatic endothelial cells first pool in the wound region following the lymph flow and then, once sufficiently populated, start to form a network. Here we present two PDE models describing lymphangiogenesis according to these two different hypotheses. Further, we include the effect of advection due to interstitial flow and lymph flow coming from open capillaries. The variables represent different cell densities and growth factor concentrations, and where possible the parameters are estimated from biological data. The models are then solved numerically and the results are compared with the available biological literature.Comment: 29 pages, 9 Figures, 6 Tables (39 figure files in total

Risk Factors and Outcomes of Candidemia Caused by Biofilm-Forming Isolates in a Tertiary Care Hospital

Very few data exist on risk factors for developing biofilm-forming Candida bloodstream infection (CBSI) or on variables associated with the outcome of patients treated for this infection. METHODS AND FINDINGS: We identified 207 patients with CBSI, from whom 84 biofilm-forming and 123 non biofilm-forming Candida isolates were recovered. A case-case-control study to identify risk factors and a cohort study to analyze outcomes were conducted. In addition, two sub-groups of case patients were analyzed after matching for age, sex, APACHE III score, and receipt of adequate antifungal therapy. Independent predictors of biofilm-forming CBSI were presence of central venous catheter (odds ratio [OR], 6.44; 95% confidence interval [95% CI], 3.21-12.92) or urinary catheter (OR, 2.40; 95% CI, 1.18-4.91), use of total parenteral nutrition (OR, 5.21; 95% CI, 2.59-10.48), and diabetes mellitus (OR, 4.47; 95% CI, 2.03-9.83). Hospital mortality, post-CBSI hospital length of stay (LOS) (calculated only among survivors), and costs of antifungal therapy were significantly greater among patients infected by biofilm-forming isolates than those infected by non-biofilm-forming isolates. Among biofilm-forming CBSI patients receiving adequate antifungal therapy, those treated with highly active anti-biofilm (HAAB) agents (e.g., caspofungin) had significantly shorter post-CBSI hospital LOS than those treated with non-HAAB antifungal agents (e.g., fluconazole); this difference was confirmed when this analysis was conducted only among survivors. After matching, all the outcomes were still favorable for patients with non-biofilm-forming CBSI. Furthermore, the biofilm-forming CBSI was significantly associated with a matched excess risk for hospital death of 1.77 compared to non-biofilm-forming CBSI. CONCLUSIONS: Our data show that biofilm growth by Candida has an adverse impact on clinical and economic outcomes of CBSI. Of note, better outcomes were seen for those CBSI patients who received HAAB antifungal therapy

Dual targeting of p53 and c-MYC selectively eliminates leukaemic stem cells

e Glasgow and Manchester Experimental Cancer Medicine Centres (ECMC), which are funded by CR-UK and the Chief Scientist’s Office (Scotland). We acknowledge the funders who have contributed to this work: MRC stratified medicine infrastructure award (A.D.W.), CR-UK C11074/A11008 (F.P., L.E.M.H., T.L.H., A.D.W.); LLR08071 (S.A.A., E.C.); LLR11017 (M.C.); SCD/04 (M.C.); LLR13035 (S.A.A., K.D., A.D.W., and A.P.); LLR14005 (M.T.S., D.V.); KKL690 (L.E.P.); KKL698 (P.B.); LLR08004 (A.D.W., A.P. and A.J.W.); MRC CiC (M.E.D.); The Howat Foundation (FACS support); Friends of Paul O’Gorman (K.D. and FACS support); ELF 67954 (S.A.A.); BSH start up fund (S.A.A.); MR/K014854/1 (K.D.)

Promoting Patient Safety and Preventing Medical Error in Emergency Departments

An estimated 108,000 people die each year from potentially preventable iatrogenic injury. One in 50 hospitalized patients experiences a preventable adverse event. Up to 3% of these injuries and events take place in emergency departments. With long and detailed training, morbidity and mortality conferences, and an emphasis on practitioner responsibility, medicine has traditionally faced the challenges of medical error and patient safety through an approach focused almost exclusively on individual practitioners. Yet no matter how well trained and how careful health care providers are, individuals will make mistakes because they are human. In general medicine, the study of adverse drug events has led the way to new methods of error detection and error prevention. A combination of chart reviews, incident logs, observation, and peer solicitation has provided a quantitative tool to demonstrate the effectiveness of interventions such as computer order entry and pharmacist order review. In emergency medicine (EM), error detection has focused on subjects of high liability: missed myocardial infarctions, missed appendicitis, and misreading of radiographs. Some system-level efforts in error prevention have focused on teamwork, on strengthening communication between pharmacists and emergency physicians, on automating drug dosing and distribution, and on rationalizing shifts. This article reviews the definitions, detection, and presentation of error in medicine and EM. Based on review of the current literature, recommendations are offered to enhance the likelihood of reduction of error in EM practice.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/74930/1/j.1553-2712.2000.tb00466.x.pd

New materials and devices for preventing catheter-related infections

Catheters are the leading source of bloodstream infections for patients in the intensive care unit (ICU). Comprehensive unit-based programs have proven to be effective in decreasing catheter-related bloodstream infections (CR-BSIs). ICU rates of CR-BSI higher than 2 per 1,000 catheter-days are no longer acceptable. The locally adapted list of preventive measures should include skin antisepsis with an alcoholic preparation, maximal barrier precautions, a strict catheter maintenance policy, and removal of unnecessary catheters. The development of new technologies capable of further decreasing the now low CR-BSI rate is a major challenge. Recently, new materials that decrease the risk of skin-to-vein bacterial migration, such as new antiseptic dressings, were extensively tested. Antimicrobial-coated catheters can prevent CR-BSI but have a theoretical risk of selecting resistant bacteria. An antimicrobial or antiseptic lock may prevent bacterial migration from the hub to the bloodstream. This review discusses the available knowledge about these new technologies

Congruence and diversity of butterfly-host plant associations at higher taxonomic levels

We aggregated data on butterfly-host plant associations from existing sources in order to address the following questions: (1) is there a general correlation between host diversity and butterfly species richness?, (2) has the evolution of host plant use followed consistent patterns across butterfly lineages?, (3) what is the common ancestral host plant for all butterfly lineages? The compilation included 44,148 records from 5,152 butterfly species (28.6% of worldwide species of Papilionoidea) and 1,193 genera (66.3%). The overwhelming majority of butterflies use angiosperms as host plants. Fabales is used by most species (1,007 spp.) from all seven butterfly families and most subfamilies, Poales is the second most frequently used order, but is mostly restricted to two species-rich subfamilies: Hesperiinae (56.5% of all Hesperiidae), and Satyrinae (42.6% of all Nymphalidae). We found a significant and strong correlation between host plant diversity and butterfly species richness. A global test for congruence (Parafit test) was sensitive to uncertainty in the butterfly cladogram, and suggests a mixed system with congruent associations between Papilionidae and magnoliids, Hesperiidae and monocots, and the remaining subfamilies with the eudicots (fabids and malvids), but also numerous random associations. The congruent associations are also recovered as the most probable ancestral states in each node using maximum likelihood methods. The shift from basal groups to eudicots appears to be more likely than the other way around, with the only exception being a Satyrine-clade within the Nymphalidae that feed on monocots. Our analysis contributes to the visualization of the complex pattern of interactions at superfamily level and provides a context to discuss the timing of changes in host plant utilization that might have promoted diversification in some butterfly lineages