Engineered bacteriophages for treatment of a patient with a disseminated drug-resistant Mycobacterium abscessus

A 15-year-old patient with cystic fibrosis with a disseminated Mycobacterium abscessus infection was treated with a three-phage cocktail following bilateral lung transplantation. Effective lytic phage derivatives that efficiently kill the infectious M. abscessus strain were developed by genome engineering and forward genetics. Intravenous phage treatment was well tolerated and associated with objective clinical improvement, including sternal wound closure, improved liver function, and substantial resolution of infected skin nodules

The anti-inflammatory effects of dimethyl fumarate in astrocytes involve glutathione and haem oxygenase-1

DMF (dimethyl fumarate) exerts anti-inflammatory and pro-metabolic effects in a variety of cell types, and a formulation (BG-12) is being evaluated for monotherapy in multiple sclerosis patients. DMF modifies glutathione (GSH) levels that can induce expression of the anti-inflammatory protein HO-1 (haem oxygenase-1). In primary astrocytes and C6 glioma cells, BG-12 dose-dependently suppressed nitrite production induced by either LI [LPS (lipopolysaccharide) at 1 \u3bcg/ml plus IFN\u3b3 (interferon \u3b3) at 20 units/ml] or a mixture of pro-inflammatory cytokines, with greater efficacy in C6 cells. BG-12 reduced NOS2 (nitric oxide synthase 2) mRNA levels and activation of a NOS2 promoter, reduced nuclear levels of NF-\u3baB (nuclear factor \u3baB) p65 subunit and attenuated loss of I\u3baB\u3b1 (inhibitory \u3baB\u3b1) in both cell types, although with greater effects in astrocytes. In astrocytes, LI decreased mRNA levels for GSHr (GSH reductase) and GCL (c-glutamylcysteine synthetase), and slightly suppressed GSHs (GSH synthetase) mRNAs. Co-treatment with BG-12 prevented those decreased and increased levels above control values. In contrast, LI reduced GSHp (GSH peroxidase) and GCL in C6 cells, and BG-12 had no effect on those levels. BG-12 increased nuclear levels of Nrf2 (nuclear factor-erythroid 2 p45 subunit-related factor 2), an inducer of GSH-related enzymes, in astrocytes but not C6 cells. In astrocytes, GSH was decreased by BG-12 at 2 h and increased at 24 h. Prior depletion of GSH using buthionine-sulfoximine increased the ability of BG-12 to reduce nitrites. In astrocytes, BG-12 increased HO-1 mRNA levels and effects on nitrite levels were blocked by an HO-1 inhibitor. These results demonstrate that BG-12 suppresses inflammatory activation in astrocytes and C6 glioma cells, but with distinct mechanisms, different dependence on GSH and different effects on transcription factor activation

Mindfulness-based interventions for young offenders: a scoping review

Youth offending is a problem worldwide. Young people in the criminal justice system have frequently experienced adverse childhood circumstances, mental health problems, difficulties regulating emotions and poor quality of life. Mindfulness-based interventions can help people manage problems resulting from these experiences, but their usefulness for youth offending populations is not clear. This review evaluated existing evidence for mindfulness-based interventions among such populations. To be included, each study used an intervention with at least one of the three core components of mindfulness-based stress reduction (breath awareness, body awareness, mindful movement) that was delivered to young people in prison or community rehabilitation programs. No restrictions were placed on methods used. Thirteen studies were included: three randomized controlled trials, one controlled trial, three pre-post study designs, three mixed-methods approaches and three qualitative studies. Pooled numbers (n = 842) comprised 99% males aged between 14 and 23. Interventions varied so it was not possible to identify an optimal approach in terms of content, dose or intensity. Studies found some improvement in various measures of mental health, self-regulation, problematic behaviour, substance use, quality of life and criminal propensity. In those studies measuring mindfulness, changes did not reach statistical significance. Qualitative studies reported participants feeling less stressed, better able to concentrate, manage emotions and behaviour, improved social skills and that the interventions were acceptable. Generally low study quality limits the generalizability of these findings. Greater clarity on intervention components and robust mixed-methods evaluation would improve clarity of reporting and better guide future youth offending prevention programs

Bilateral Assessment of Functional Tasks for Robot-assisted Therapy Applications

This article presents a novel evaluation system along with methods to evaluate bilateral coordination of arm function on activities of daily living tasks before and after robot-assisted therapy. An affordable bilateral assessment system (BiAS) consisting of two mini-passive measuring units modeled as three degree of freedom robots is described. The process for evaluating functional tasks using the BiAS is presented and we demonstrate its ability to measure wrist kinematic trajectories. Three metrics, phase difference, movement overlap, and task completion time, are used to evaluate the BiAS system on a bilateral symmetric (bi-drink) and a bilateral asymmetric (bi-pour) functional task. Wrist position and velocity trajectories are evaluated using these metrics to provide insight into temporal and spatial bilateral deficits after stroke. The BiAS system quantified movements of the wrists during functional tasks and detected differences in impaired and unimpaired arm movements. Case studies showed that stroke patients compared to healthy subjects move slower and are less likely to use their arm simultaneously even when the functional task requires simultaneous movement. After robot-assisted therapy, interlimb coordination spatial deficits moved toward normal coordination on functional tasks

Effect of mechanical preconditioning on the electrical properties of knitted conductive textiles during cyclic loading

This paper presents, for the first time, the electrical response of knitted conductive fabrics to a considerable number of cycles of deformation in view of their use as wearable sensors. The changes in the electrical properties of four knitted conductive textiles, made of 20% stainless steel and 80% polyester fibers, were studied during unidirectional elongation in an Instron machine. Two tests sessions of 250 stretch–recovery cycles were conducted for each sample at two elongation rates (9.6 and 12 mm/s) and at three constant currents (1, 3 and 6 mA). The first session assessed the effects of an extended cyclic mechanical loading (preconditioning) on the electrical properties, especially on the electrical stabilization. The second session, which followed after a 5 minute interval under identical conditions, investigated whether the stabilization and repeatability of the electrical features were maintained after rest. The influence of current and elongation rate on the resistance measurements was also analyzed. In particular, the presence of a semiconducting behavior of the stainless steel fibers was proved by means of different test currents. Lastly, the article shows the time-dependence of the fabrics by means of hysteresis graphs and their non-linear behavior thanks to a time–frequency analysis. All knit patterns exhibited interesting changes in electrical properties as a result of mechanical preconditioning and extended use. For instance, the gauge factor, which indicates the sensitivity of the fabric sensor, varied considerably with the number of cycles, being up to 20 times smaller than that measured using low cycle number protocols

Antioxidant activities and phenolic contents of the methanol extracts of the stems of Acokanthera oppositifolia and Adenia gummifera

Abstract Background Acokanthera oppositifolia Lam (family: Apocynaceae) is a shrub or small tree with white latex, and the leaves of this plant are used in the form of a snuff to treat headaches and in infusions for abdominal pains and convulsions and septicaemia. Adenia gummifera Harv of the family Passifloraceae is a distinctive woody climber whose infusions are used as emetics and are said to help with some forms of depression. Lipid peroxidation has gained more importance today because of its involvement in pathogenesis of many diseases. Free radicals are the main agents in lipid peroxidation. Antioxidants thus play an important role of protecting the human body against damage by the free radicals. Plants containing phenolic compounds have been reported to possess strong antioxidant properties. Methods The antioxidant activities and phenolic contents of the methanol extracts of the stems of Acokanthera oppositifolia and Adenia gummifera were evaluated using in vitro standard procedures. Spectrophotometry was the basis for the determinations of total phenol, total flavonoids, flavonols, and proanthocyanidins. Tannins, quercetin and catechin equivalents were used for these parameters. The antioxidant activities of the stem extract of Acokanthera oppositifolia were determined by the 2,2'-azinobis-3- ethylbenzothiazoline-6-sulfonic acid (ABTS), 1,1-Diphenyl-2-picrylhydrazyl (DPPH), and ferrous reducing antioxidant property (FRAP) methods. Results The results from this study showed that the antioxidant activities of the stem extract of Acokanthera oppositifolia as determined by the 1,1-Diphenyl-2-picrylhydrazyl (DPPH), and ferrous reducing antioxidant property (FRAP) methods, were higher than that of Adenia gummifera. The levels of total phenols and flavonols for A. oppositifolia were also higher. On the other hand, the stem extract of Adenia gummifera had higher level of total flavonoids and proanthocyanidins than that of Acokanthera oppositifolia. The 2, 2'-azinobis-3- ethylbenzothiazoline-6-sulfonic acid (ABTS) activities of the 2 plant extracts were similar and comparable to that of BHT. Conclusion Thus, the present results indicate clearly that the extracts of Acokanthera oppositifolia and Adenia gummifera possess antioxidant properties and could serve as free radical inhibitors or scavengers, acting possibly as primary antioxidants. This study has to some extent validated the medicinal potential of the stems of Acokanthera oppositifolia and Adenia gummifera.</p

Contribution of CTCF binding to transcriptional activity at the HOXA locus in NPM1-mutant AML cells

Transcriptional regulation of the HOXA genes is thought to involve CTCF-mediated chromatin loops and the opposing actions of the COMPASS and Polycomb epigenetic complexes. We investigated the role of these mechanisms at the HOXA cluster in AML cells with the common NPM1c mutation, which express both HOXA and HOXB genes. CTCF binding at the HOXA locus is conserved across primary AML samples, regardless of HOXA gene expression, and defines a continuous chromatin domain marked by COMPASS-associated histone H3 trimethylation in NPM1-mutant primary AML samples. Profiling of the three-dimensional chromatin architecture in primary AML samples with the NPM1c mutation identified chromatin loops between the HOXA cluster and loci in the SNX10 and SKAP2 genes, and an intergenic region located 1.4 Mbp upstream of the HOXA locus. Deletion of CTCF binding sites in the NPM1-mutant OCI-AML3 AML cell line reduced multiple long-range interactions, but resulted in CTCF-independent loops with sequences in SKAP2 that were marked by enhancer-associated histone modifications in primary AML samples. HOXA gene expression was maintained in CTCF binding site mutants, indicating that transcriptional activity at the HOXA locus in NPM1-mutant AML cells may be sustained through persistent interactions with SKAP2 enhancers, or by intrinsic factors within the HOXA gene cluster

Widespread active detachment faulting and core complex formation near 13°N on the Mid-Atlantic Ridge

Author Posting. © Nature Publishing Group, 2006. This is the author's version of the work. It is posted here by permission of Nature Publishing Group for personal use, not for redistribution. The definitive version was published in Nature 442 (2006): 440-443, doi:10.1038/nature04950.Oceanic core complexes are massifs in which lower crustal and upper mantle rocks are exposed at the sea floor. They form at mid-ocean ridges through slip on detachment faults rooted below the spreading axis. To date, most studies of core complexes have been based on isolated inactive massifs that have spread away from ridge axes. A new survey of the Mid-Atlantic Ridge (MAR) near 13°N reveals a segment in which a number of linked detachment faults extend for 75 km along one flank of the spreading axis. The detachment faults are apparently all currently active and at various stages of development. A field of extinct core complexes extends away from the axis for at least 100 km. The new data document the topographic characteristics of actively-forming core complexes and their evolution from initiation within the axial valley floor to maturity and eventual inactivity. Within the surrounding region there is a strong correlation between detachment fault morphology at the ridge axis and high rates of hydroacoustically-recorded earthquake seismicity. Preliminary examination of seismicity and seafloor morphology farther north along the MAR suggests that active detachment faulting is occurring in many segments and that detachment faulting is more important in the generation of ocean crust at this slow-spreading ridge than previously suspected.This work was supported by the National Science Foundation