Evaluation of Filesystem Provenance Visualization Tools

Having effective visualizations of filesystem provenance data is valuable for understanding its complex hierarchical structure. The most common visual representation of provenance data is the node-link diagram. While effective for understanding local activity, the node-link diagram fails to offer a high-level summary of activity and inter-relationships within the data. We present a new tool, InProv, which displays filesystem provenance with an interactive radial-based tree layout. The tool also utilizes a new time-based hierarchical node grouping method for filesystem provenance data we developed to match the user’s mental model and make data exploration more intuitive. We compared InProv to a conventional node-link based tool, Orbiter, in a quantitative evaluation with real users of filesystem provenance data including provenance data experts, IT professionals, and computational scientists. We also compared in the evaluation our new node grouping method to a conventional method. The results demonstrate that InProv results in higher accuracy in identifying system activity than Orbiter with large complex data sets. The results also show that our new time- based hierarchical node grouping method improves performance in both tools, and participants found both tools significantly easier to use with the new time-based node grouping method. Subjective measures show that participants found InProv to require less mental activity, less physical activity, less work, and is less stressful to use. Our study also reveals one of the first cases of gender differences in visualization; both genders had comparable performance with InProv, but women had a significantly lower average accuracy (56%) compared to men (70%) with Orbiter.Engineering and Applied Science

Janus Molecule I: Dichotomous Effects of COMT in Neuropathic vs Nociceptive Pain Modalities

The enzyme catechol-O-methyltransferase (COMT) has been shown to play a critical role in pain perception by regulating levels of epinephrine (Epi) and norepinephrine (NE). Although the key contribution of catecholamines to the perception of pain has been recognized for a long time, there is a clear dichotomy of observations. More than a century of research has demonstrated that increasing adrenergic transmission in the spinal cord decreases pain sensitivity in animals. Equally abundant evidence demonstrates the opposite effect of adrenergic signaling in the peripheral nervous system, where adrenergic signaling increases pain sensitivity. Viewing pain processing within spinal and peripheral compartments and determining the directionality of adrenergic signaling helps clarify the seemingly contradictory findings of the pain modulatory properties of adrenergic receptor agonists and antagonists presented in other reviews. Available evidence suggests that adrenergic signaling contributes to pain phenotypes through α 1/2 and β 2/3 receptors. While stimulation of α 2 adrenergic receptors seems to uniformly produce analgesia, stimulation of α 1 or β receptors produces either analgesic or hyperalgesic effects. Establishing the directionality of adrenergic receptor modulation of pain processing, and related COMT activity in different pain models are needed to bring meaning to recent human molecular genetic findings. This will enable the translation of current findings into meaningful clinical applications such as diagnostic markers and novel therapeutic targets for complex human pain conditions

Randomized, double-blind comparison of once-weekly dalbavancin versus twice-daily linezolid therapy for the treatment of complicated skin and skin structure infections

Background. Dalbavancin, a novel lipoglycopeptide with a pharmacokinetic profile that allows weekly dosing, is active against gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). The efficacy of dalbavancin for treatment of skin and skin structure infections (SSSIs) was demonstrated in a phase 2 study. Methods. In a phase 3 noninferiority study, patients with complicated SSSIs, including infections known or suspected to involve MRSA, were randomized (ratio, 2:1) in a double-blind manner to receive dalbavancin (1000 mg given intravenously on day 1 and 500 mg given intravenously on day 8) or linezolid (600 mg given intravenously or intravenously/orally every 12 h for 14 days). Efficacy was assessed by determining clinical and microbiological responses at the end of therapy and at the test-of-cure visit. Relapses were identified by additional follow-up ~1 month later. Results. MRSA was identified in 51% of patients from whom a pathogen was isolated at baseline. Dalbavancin and linezolid demonstrated comparable clinical efficacy in the clinically evaluable population at the test-of-cure visit (88.9% and 91.2% success, respectively). The rate of clinical success at the end of therapy was >90% in both arms. Less than 1.0% of patients in either treatment arm experienced relapse after the test-of-cure visit. Both treatments yielded successful microbiological response in excess of 85% among microbiologically evaluable patients at end of therapy and at the test-of-cure visit for all pathogens combined, for all S. aureus strains, and for MRSA. Gastrointestinal symptoms were among the most common adverse events in both arms. A higher proportion of patients in the linezolid arm reported adverse events that were judged by the investigator to be probably/possibly related to treatment (dalbavancin arm, 25.4% of subjects; linezolid arm, 32.2% of subjects). Conclusions. Two doses of dalbavancin (1000 mg given on day 1 followed by 500 mg given on day 8) were as well tolerated and as effective as linezolid given twice daily for 14 days for the treatment of patients with complicated SSSI, including those infected with MRSA.Peer reviewe

Cooling effect in emissions of 103mRh excited by bremsstrahlung

Nonlinear characteristic emissions of K alpha, K beta and gamma with a significant triplet splitting at room temperature are observed from the long-lived nuclear state of 103mRh excited by bremsstrahlung irradiation. A pronounced phase-transition-like narrowing of the emission profiles occurs immediately after the sample is cooled down to 77 K. The room temperature profiles reappear again abruptly and almost reversibly as the temperature drifts freely back to approximately the ice point after the filling of liquid nitrogen is stopped. These emission properties at 300 K and at low temperature may indicate that the 103mRh nuclei are in collective states

Optical Magnetometry

Some of the most sensitive methods of measuring magnetic fields utilize interactions of resonant light with atomic vapor. Recent developments in this vibrant field are improving magnetometers in many traditional areas such as measurement of geomagnetic anomalies and magnetic fields in space, and are opening the door to new ones, including, dynamical measurements of bio-magnetic fields, detection of nuclear magnetic resonance (NMR), magnetic-resonance imaging (MRI), inertial-rotation sensing, magnetic microscopy with cold atoms, and tests of fundamental symmetries of Nature.Comment: 11 pages; 4 figures; submitted to Nature Physic

Evolutionary Patterning: A Novel Approach to the Identification of Potential Drug Target Sites in Plasmodium falciparum

Malaria continues to be the most lethal protozoan disease of humans. Drug development programs exhibit a high attrition rate and parasite resistance to chemotherapeutic drugs exacerbates the problem. Strategies that limit the development of resistance and minimize host side-effects are therefore of major importance. In this study, a novel approach, termed evolutionary patterning (EP), was used to identify suitable drug target sites that would minimize the emergence of parasite resistance. EP uses the ratio of non-synonymous to synonymous substitutions (ω) to assess the patterns of evolutionary change at individual codons in a gene and to identify codons under the most intense purifying selection (ω≤0.1). The extreme evolutionary pressure to maintain these residues implies that resistance mutations are highly unlikely to develop, which makes them attractive chemotherapeutic targets. Method validation included a demonstration that none of the residues providing pyrimethamine resistance in the Plasmodium falciparum dihydrofolate reductase enzyme were under extreme purifying selection. To illustrate the EP approach, the putative P. falciparum glycerol kinase (PfGK) was used as an example. The gene was cloned and the recombinant protein was active in vitro, verifying the database annotation. Parasite and human GK gene sequences were analyzed separately as part of protozoan and metazoan clades, respectively, and key differences in the evolutionary patterns of the two molecules were identified. Potential drug target sites containing residues under extreme evolutionary constraints were selected. Structural modeling was used to evaluate the functional importance and drug accessibility of these sites, which narrowed down the number of candidates. The strategy of evolutionary patterning and refinement with structural modeling addresses the problem of targeting sites to minimize the development of drug resistance. This represents a significant advance for drug discovery programs in malaria and other infectious diseases

Physiological properties of enkephalin-containing neurons in the spinal dorsal horn visualized by expression of green fluorescent protein in BAC transgenic mice

<p>Abstract</p> <p>Background</p> <p>Enkephalins are endogenous opiates that are assumed to modulate nociceptive information by mediating synaptic transmission in the central nervous system, including the spinal dorsal horn.</p> <p>Results</p> <p>To develop a new tool for the identification of <it>in vitro </it>enkephalinergic neurons and to analyze enkephalin promoter activity, we generated transgenic mice for a bacterial artificial chromosome (BAC). Enkephalinergic neurons from these mice expressed enhanced green fluorescent protein (eGFP) under the control of the preproenkephalin (PPE) gene (<it>penk1</it>) promoter. eGFP-positive neurons were distributed throughout the gray matter of the spinal cord, and were primarily observed in laminae I-II and V-VII, in a pattern similar to the distribution pattern of enkephalin-containing neurons. Double immunostaining analysis using anti-enkephalin and anti-eGFP antibodies showed that all eGFP-expressing neurons contained enkephalin. Incubation in the presence of forskolin, an activator of adenylate cyclase, increased the number of eGFP-positive neurons. These results indicate that eGFP expression is controlled by the <it>penk1 </it>promoter, which contains cyclic AMP-responsive elements. Sections obtained from sciatic nerve-ligated mice exhibited increased eGFP-positive neurons on the ipsilateral (nerve-ligated side) compared with the contralateral (non-ligated side). These data indicate that PPE expression is affected by peripheral nerve injury. Additionally, single-neuron RT-PCR analysis showed that several eGFP positive-neurons in laminae I-II expressed glutamate decarboxylase 67 mRNA and that some expressed serotonin type 3 receptors.</p> <p>Conclusions</p> <p>These results suggest that eGFP-positive neurons in laminae I-II coexpress enkephalin and γ-aminobutyric acid (GABA), and are activated by forskolin and in conditions of nerve injury. The <it>penk1</it>-eGFP BAC transgenic mouse contributes to the further characterization of enkephalinergic neurons in the transmission and modulation of nociceptive information.</p

Metabolic regulation by p53

We are increasingly aware that cellular metabolism plays a vital role in diseases such as cancer, and that p53 is an important regulator of metabolic pathways. By transcriptional activation and other means, p53 is able to contribute to the regulation of glycolysis, oxidative phosphorylation, glutaminolysis, insulin sensitivity, nucleotide biosynthesis, mitochondrial integrity, fatty acid oxidation, antioxidant response, autophagy and mTOR signalling. The ability to positively and negatively regulate many of these pathways, combined with feedback signalling from these pathways to p53, demonstrates the reciprocal and flexible nature of the regulation, facilitating a diverse range of responses to metabolic stress. Intriguingly, metabolic stress triggers primarily an adaptive (rather than pro-apoptotic) p53 response, and p53 is emerging as an important regulator of metabolic homeostasis. A better understanding of how p53 coordinates metabolic adaptation will facilitate the identification of novel therapeutic targets and will also illuminate the wider role of p53 in human biology

Neuropathic Pain in Rats with a Partial Sciatic Nerve Ligation Is Alleviated by Intravenous Injection of Monoclonal Antibody to High Mobility Group Box-1

High mobility group box-1 (HMGB1) is associated with the pathogenesis of inflammatory diseases. A previous study reported that intravenous injection of anti-HMGB1 monoclonal antibody significantly attenuated brain edema in a rat model of stroke, possibly by attenuating glial activation. Peripheral nerve injury leads to increased activity of glia in the spinal cord dorsal horn. Thus, it is possible that the anti-HMGB1 antibody could also be efficacious in attenuating peripheral nerve injury-induced pain. Following partial sciatic nerve ligation (PSNL), rats were treated with either anti-HMGB1 or control IgG. Intravenous treatment with anti-HMGB1 monoclonal antibody (2 mg/kg) significantly ameliorated PSNL-induced hind paw tactile hypersensitivity at 7, 14 and 21 days, but not 3 days, after ligation, whereas control IgG had no effect on tactile hypersensitivity. The expression of HMGB1 protein in the spinal dorsal horn was significantly increased 7, 14 and 21 days after PSNL; the efficacy of the anti-HMGB1 antibody is likely related to the presence of HMGB1 protein. Also, the injury-induced translocation of HMGB1 from the nucleus to the cytosol occurred mainly in dorsal horn neurons and not in astrocytes and microglia, indicating a neuronal source of HMGB1. Markers of astrocyte (glial fibrillary acidic protein (GFAP)), microglia (ionized calcium binding adaptor molecule 1 (Iba1)) and spinal neuron (cFos) activity were greatly increased in the ipsilateral dorsal horn side compared to the sham-operated side 21 days after PSNL. Anti-HMGB1 monoclonal antibody treatment significantly decreased the injury-induced expression of cFos and Iba1, but not GFAP. The results demonstrate that nerve injury evokes the synthesis and release of HMGB1 from spinal neurons, facilitating the activity of both microglia and neurons, which in turn leads to symptoms of neuropathic pain. Thus, the targeting of HMGB1 could be a useful therapeutic strategy in the treatment of chronic pain