Bacterial toxin-triggered release of antibiotics from capsosomes protects a fly model from lethal methicillin-resistant Staphylococcus aureus (MRSA) infection

Antibiotic resistance is a severe global health threat and hence demands rapid action to develop novel therapies, including microscale drug delivery systems. Herein, a hierarchical microparticle system is developed to achieve bacteria-activated single- and dual-antibiotic drug delivery for preventing methicillin-resistant Staphylococcus aureus (MRSA) bacterial infections. The designed system is based on a capsosome structure, which consists of a mesoporous silica microparticle coated in alternating layers of oppositely charged polymers and antibiotic-loaded liposomes. The capsosomes are engineered and shown to release their drug payloads in the presence of MRSA toxins controlled by the Agr quorum sensing system. MRSA-activated single drug delivery of vancomycin and synergistic dual delivery of vancomycin together with an antibacterial peptide successfully kills MRSA in vitro. The capability of capsosomes to selectively deliver their cargo in the presence of bacteria, producing a bactericidal effect to protect the host organism, is confirmed in vivo using a Drosophila melanogaster MRSA infection model. Thus, the capsosomes serve as a versatile multidrug, subcompartmentalized microparticle system for preventing antibiotic-resistant bacterial infections, with potential applications to protect wounds or medical device implants from infections

Lethality and Developmental Delay in Drosophila melanogaster Larvae after Ingestion of Selected Pseudomonas fluorescens Strains

The fruit fly, Drosophila melanogaster, is a well-established model organism for probing the molecular and cellular basis of physiological and immune system responses of adults or late stage larvae to bacterial challenge. However, very little is known about the consequences of bacterial infections that occur in earlier stages of development. We have infected mid-second instar larvae with strains of Pseudomonas fluorescens to determine how infection alters the ability of larvae to survive and complete development.We mimicked natural routes of infection using a non-invasive feeding procedure to study the toxicity of the three sequenced P. fluorescens strains (Pf0-1, SBW25, and Pf-5) to Drosophila melanogaster. Larvae fed with the three strains of P. fluorescens showed distinct differences in developmental trajectory and survival. Treatment with SBW25 caused a subset of insects to die concomitant with a systemic melanization reaction at larval, pupal or adult stages. Larvae fed with Pf-5 died in a dose-dependent manner with adult survivors showing eye and wing morphological defects. In addition, larvae in the Pf-5 treatment groups showed a dose-dependent delay in the onset of metamorphosis relative to control-, Pf0-1-, and SBW25-treated larvae. A functional gacA gene is required for the toxic properties of wild-type Pf-5 bacteria.These experiments are the first to demonstrate that ingestion of P. fluorescens bacteria by D. melanogaster larvae causes both lethal and non-lethal phenotypes, including delay in the onset of metamorphosis and morphological defects in surviving adult flies, which can be decoupled

The Imd Pathway Is Involved in Antiviral Immune Responses in Drosophila

Cricket Paralysis virus (CrPV) is a member of the Dicistroviridae family of RNA viruses, which infect a broad range of insect hosts, including the fruit fly Drosophila melanogaster. Drosophila has emerged as an effective system for studying innate immunity because of its powerful genetic techniques and the high degree of gene and pathway conservation. Intra-abdominal injection of CrPV into adult flies causes a lethal infection that provides a robust assay for the identification of mutants with altered sensitivity to viral infection. To gain insight into the interactions between viruses and the innate immune system, we injected wild type flies with CrPV and observed that antimicrobial peptides (AMPs) were not induced and hemocytes were depleted in the course of infection. To investigate the contribution of conserved immune signaling pathways to antiviral innate immune responses, CrPV was injected into isogenic mutants of the Immune Deficiency (Imd) pathway, which resembles the mammalian Tumor Necrosis Factor Receptor (TNFR) pathway. Loss-of-function mutations in several Imd pathway genes displayed increased sensitivity to CrPV infection and higher CrPV loads. Our data show that antiviral innate immune responses in flies infected with CrPV depend upon hemocytes and signaling through the Imd pathway

The Role of Anorexia in Resistance and Tolerance to Infections in Drosophila

Infections initiate a signaling loop in which sick animals become anorexic, and the resulting change in diet alters the body's ability to fight infections in good and bad ways

Predictors of stable return-to-work in non-acute, non-specific spinal pain: low total prior sick-listing, high self prediction and young age. A two-year prospective cohort study

<p>Abstract</p> <p>Background</p> <p>Non-specific spinal pain (NSP), comprising back and/or neck pain, is one of the leading disorders in long-term sick-listing. During 2000-2004, 125 Swedish primary-care patients with non-acute NSP, full-time sick-listed 6 weeks-2 years, were included in a randomized controlled trial to compare a cognitive-behavioural programme with traditional primary care. This prospective cohort study is a re-assessment of the data from the randomized trial with the 2 treatment groups considered as a single cohort. The aim was to investigate which baseline variables predict a stable return-to-work during a 2-year period after baseline: objective variables from function tests, socioeconomic, subjective and/or treatment variables. Stable return-to-work was a return-to-work lasting for at least 1 month from the start of follow-up.</p> <p>Methods</p> <p><it>Stable return-to-work </it>was the outcome variable, the above-mentioned factors were the predictive variables in multiple-logistic regression models, one per follow-up at 6, 12, 18 and 24 months after baseline. The factors from univariate analyzes with a <it>p</it>-value of at most .10 were included. The non-significant variables were excluded stepwise to yield models comprising only significant factors (<it>p </it>< .05). As the comparatively few cases made it risky to associate certain predictors with certain time-points, we finally considered the predictors which were represented in at least 3 follow-ups. They are presented with odds ratios (OR) and 95% confidence intervals.</p> <p>Results</p> <p>Three variables qualified, all of them represented in 3 follow-ups: <it>Low total prior sick-listing </it>(including all diagnoses) was the strongest predictor in 2 follow-ups, 18 and 24 months, OR 4.8 [1.9-12.3] and 3.8 [1.6-8.7] respectively, <it>High self prediction </it>(the patients' own belief in return-to-work) was the strongest at 12 months, OR 5.2 [1.5-17.5] and <it>Young age </it>(max 44 years) the second strongest at 18 months, OR 3.5 [1.3-9.1].</p> <p>Conclusions</p> <p>In primary-care patients with non-acute NSP, the strong predictors of stable return-to-work were 2 socioeconomic variables, <it>Low total prior sick-listing </it>and <it>Young age</it>, and 1 subjective variable, <it>High self-prediction</it>. Objective variables from function tests and treatment variables were non-predictors. Except for <it>Young age</it>, the predictors have previously been insufficiently studied, and so our study should widen knowledge within clinical practice.</p> <p>Trial registration</p> <p>Trial registration number for the original trial NCT00488735.</p

A shared role for RBF1 and dCAP-D3 in the regulation of transcription with consequences for innate immunity

Previously, we discovered a conserved interaction between RB proteins and the Condensin II protein CAP-D3 that is important for ensuring uniform chromatin condensation during mitotic prophase. The Drosophila melanogaster homologs RBF1 and dCAP-D3 co-localize on non-dividing polytene chromatin, suggesting the existence of a shared, non-mitotic role for these two proteins. Here, we show that the absence of RBF1 and dCAP-D3 alters the expression of many of the same genes in larvae and adult flies. Strikingly, most of the genes affected by the loss of RBF1 and dCAP-D3 are not classic cell cycle genes but are developmentally regulated genes with tissue-specific functions and these genes tend to be located in gene clusters. Our data reveal that RBF1 and dCAP-D3 are needed in fat body cells to activate transcription of clusters of antimicrobial peptide (AMP) genes. AMPs are important for innate immunity, and loss of either dCAP-D3 or RBF1 regulation results in a decrease in the ability to clear bacteria. Interestingly, in the adult fat body, RBF1 and dCAP-D3 bind to regions flanking an AMP gene cluster both prior to and following bacterial infection. These results describe a novel, non-mitotic role for the RBF1 and dCAP-D3 proteins in activation of the Drosophila immune system and suggest dCAP-D3 has an important role at specific subsets of RBF1-dependent genes

A biologically inspired network design model

A network design problem is to select a subset of links in a transport network that satisfy passengers or cargo transportation demands while minimizing the overall costs of the transportation. We propose a mathematical model of the foraging behaviour of slime mould P. polycephalum to solve the network design problem and construct optimal transport networks. In our algorithm, a traffic flow between any two cities is estimated using a gravity model. The flow is imitated by the model of the slime mould. The algorithm model converges to a steady state, which represents a solution of the problem. We validate our approach on examples of major transport networks in Mexico and China. By comparing networks developed in our approach with the man-made highways, networks developed by the slime mould, and a cellular automata model inspired by slime mould, we demonstrate the flexibility and efficiency of our approach

Low back pain and widespread pain predict sickness absence among industrial workers

BACKGROUND: The prevalence of musculoskeletal disorders (MSD) in the aluminium industry is high, and there is a considerable work-related fraction. More knowledge about the predictors of sickness absence from MSD in this industry will be valuable in determining strategies for prevention. The aim of this study was to analyse the relative impact of body parts, psychosocial and individual factors as predictors for short- and long-term sickness absence from MSD among industrial workers. METHODS: A follow-up study was conducted among all the workers at eight aluminium plants in Norway. A questionnaire was completed by 5654 workers at baseline in 1998. A total of 3320 of these participated in the follow-up study in 2000. Cox regression analysis was applied to investigate the relative impact of MSD in various parts of the body and of psychosocial and individual factors reported in 1998 on short-term and long-term sickness absence from MSD reported in 2000. RESULTS: MSD accounted for 45% of all working days lost the year prior to follow-up in 2000. Blue-collar workers had significantly higher risk than white-collar workers for both short- and long-term sickness absence from MSD (long-term sickness absence: RR = 3.04, 95% CI 2.08–4.45). Widespread and low back pain in 1998 significantly predicted both short- and long-term sickness absence in 2000. In addition, shoulder pain predicted long-term sickness absence. Low social support predicted short-term sickness absence (RR = 1.28, 95% CI 1.11–1.49). CONCLUSIONS: Reducing sickness absence from MSD among industrial workers requires focusing on the working conditions of blue-collar workers and risk factors for low back pain and widespread pain. Increasing social support in the work environment may have effects in reducing short-term sickness absence from MSD