mfEGRA: Multifidelity Efficient Global Reliability Analysis through Active Learning for Failure Boundary Location

This paper develops mfEGRA, a multifidelity active learning method using data-driven adaptively refined surrogates for failure boundary location in reliability analysis. This work addresses the issue of prohibitive cost of reliability analysis using Monte Carlo sampling for expensive-to-evaluate high-fidelity models by using cheaper-to-evaluate approximations of the high-fidelity model. The method builds on the Efficient Global Reliability Analysis (EGRA) method, which is a surrogate-based method that uses adaptive sampling for refining Gaussian process surrogates for failure boundary location using a single-fidelity model. Our method introduces a two-stage adaptive sampling criterion that uses a multifidelity Gaussian process surrogate to leverage multiple information sources with different fidelities. The method combines expected feasibility criterion from EGRA with one-step lookahead information gain to refine the surrogate around the failure boundary. The computational savings from mfEGRA depends on the discrepancy between the different models, and the relative cost of evaluating the different models as compared to the high-fidelity model. We show that accurate estimation of reliability using mfEGRA leads to computational savings of $\sim$46% for an analytic multimodal test problem and 24% for a three-dimensional acoustic horn problem, when compared to single-fidelity EGRA. We also show the effect of using a priori drawn Monte Carlo samples in the implementation for the acoustic horn problem, where mfEGRA leads to computational savings of 45% for the three-dimensional case and 48% for a rarer event four-dimensional case as compared to single-fidelity EGRA

Immobilization of antibacterial dihydropyrrol-2-ones on functional polymer supports to prevent bacterial infections in vivo

Antibiotic-resistant Staphylococcus aureus is of great concern, as it causes a wide range of life-threatening infections. The current study demonstrates that dihydropyrrolone (DHP)-coated polyacrylamide substrates are effective in reducing the number of culturable clinical isolates of S. aureus in vitro in a dose-dependent manner and are able to reduce the pathogenic potential of staphylococcal infection in a subcutaneous infection model. Covalently bound DHPs therefore show great potential for use as an antimicrobial strategy in device-related applications. Copyright © 2012, American Society for Microbiology. All Rights Reserved

Variable Corticosteroid Sensitivity of Thymic Cortex and Medullary Peripheral-type Lymphoid Tissue in Myasthenia Gravis Patients: Structural and Functional Effects

The thymus has been studied in myasthenia gravis patients to assess the effects of previous immunosuppresslon on total yields of cell suspension, immunohistology and culture responses. The reduction in cell yields by pretreatment with corticosteroid was very variable. In 16 of 32 cases, cortical, medullary and total cell numbers were all greatly reduced (‘depleted cases'), whereas in the others, they were within or near the typical range for untreated myasthenics. Cortical thymocytes were even more depleted than precursor thymic blasts. Thus the interpatient differences in sensitivity to corticosteroid recently described for mature T cells also affected immature cortical thymocytes and their differentiating medullary progeny.In the medulla, mature (CD3+)T lymphocytes and germinal centres were enriched by the loss of cortex and appeared relatively healthy, but somewhat depopulated. Concomitantly, in-vitro T-cell responses to acetylcholine receptor (AChR) and production of anti-A ChR antibody and total IgG by thymic cells were usually well within the typical range (assessed per 106 cells). Moreover, the total productivity of the entire thymus was reduced almost entirely by the cellular depopulation rather than by decreased function per surviving cell. Thus the main actions of this alternate day therapy with corticosteroids were apparently on total peripheral cell numbers, and perhaps on activated cells and effector mechanisms too, and its thymic effects were inessentia

Decrease in hyperosmotic stress-induced corneal epithelial cell apoptosis by L-carnitine

Purpose: To characterize the osmoprotective properties of L-carnitine on human corneal epithelial cell volume and apoptosis during hyperosmotic stress. Methods: Human corneal limbal epithelial (HCLE) cells were exposed to culture medium at 300 mOsm (isotonic) or 500 mOsm (hyperosmotic) with or without L-carnitine (10 mM). Induction of apoptosis was detected by quantifying the proteolytic activity of caspase-8, caspase-9, and caspase-3/7 using caspase activity assays, the expression of tumor necrosis factor (TNF)-α with enzyme-linked immunosorbent assay, and annexin V/propidium iodide staining of HCLE cells evaluated with confocal microscopy and flow cytometry. Cell volume changes in response to hyperosmotic stress were analyzed using flow cytometry. Results: After the HCLE cells were exposed to hyperosmotic medium (500 mOsm), the percentage of shrunken cells and damaged/dead cells (stained positively for annexin V and/or propidium iodide) was six- and three-fold, respectively, higher than that under isotonic conditions (300 mOsm). This was paralleled by an increase in TNF-α concentration in media and caspase-8, -9, and -3/7 activities (six-, four-, ten-, and twelve-fold, respectively; all showing p\u3c0.001). Addi­tion of L-carnitine during hyperosmotic stress partly restored cell volume and significantly reduced the concentration of TNF-α released (p=0.005) and caspase-9 activity (p=0.0125). Addition of L-carnitine reduced the percentage of hyperosmolarity-induced damaged/dead cells to levels observed under isotonic conditions

Design, Synthesis and Biological Evaluation of N-Sulfonylphenyl glyoxamide-Based Antimicrobial Peptide Mimics as Novel Antimicrobial Agents

© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Antibiotic resistance is a major global health concern. There is an urgent need for the development of novel antimicrobials. Recently, phenylglyoxamide-based small molecular antimicrobial peptide mimics have been identified as potential new leads to treat bacterial infections. Here, we describe the synthesis of novel phenylglyoxamide derivatives via the ring-opening reaction of N-sulfonylisatins with primary amines, followed by conversion into hydrochloride, quaternary ammonium iodide or gunidinium salts. The antibacterial activity of the compounds against Staphylococcus aureus was evaluated by in vitro assays. Structure-activity relationship studies revealed that 5-bromo-substituent at the phenyl ring, octyl group appended to the ortho sulfonamide group or guanidine hydrochloride salt as the terminal group significantly contributed to potency. The most potent compound, the gunidinium salt 35 d, exhibited a minimum inhibitory concentration value of 12 μM and a therapeutic index of 15. It also demonstrated its potential to act as antimicrobial pore-forming agent. Overall, the results identified 35 d as a new lead antimicrobial compound

Do ethnobotanical and laboratory data predict clinical safety and efficacy of anti-malarial plants?

<p>Abstract</p> <p>Background</p> <p>Over 1200 plant species are reported in ethnobotanical studies for the treatment of malaria and fevers, so it is important to prioritize plants for further development of anti-malarials.</p> <p>Methods</p> <p>The “RITAM score” was designed to combine information from systematic literature searches of published ethnobotanical studies and laboratory pharmacological studies of efficacy and safety, in order to prioritize plants for further research. It was evaluated by correlating it with the results of clinical trials.</p> <p>Results and discussion</p> <p>The laboratory efficacy score correlated with clinical parasite clearance (r_s=0.7). The ethnobotanical component correlated weakly with clinical symptom clearance but not with parasite clearance. The safety component was difficult to validate as all plants entering clinical trials were generally considered safe, so there was no clinical data on toxic plants.</p> <p>Conclusion</p> <p>The RITAM score (especially the efficacy and safety components) can be used as part of the selection process for prioritising plants for further research as anti-malarial drug candidates. The validation in this study was limited by the very small number of available clinical studies, and the heterogeneity of patients included.</p

Microbial contamination of hydrogel contact lenses

Bacterial contamination of contact lenses (CLs) may contribute to CL-related corneal infection and inflammation. This study reports CL biota over time during daily and extended wear. Microbial contamination of a 58% water, ionic hydrogel CL and a 38% water, non-ionic hydrogel CL was evaluated in an Australian and an Indian population. Fifty wearers were repeatedly sampled over 18 months. Overnight CL use did not alter the frequency of positive cultures, nor the spectrum of organisms compared with daily CL wear. There were no differences in type and frequency of CL contamination between the CL types. Positive cultures were more frequently recovered from the Indian population compared with the Australian population. Streptococcus spp. and Propionibacterium spp. were more frequently isolated from the Australian population. Fungi and Bacillus spp. were more frequently isolated from the Indian population. Normal CL biota alone cannot explain the increased rate of infection and inflammation in extended wear

Tuning the Anthranilamide Peptidomimetic Design to Selectively Target Planktonic Bacteria and Biofilm

There is a pressing need to develop new antimicrobials to help combat the increase in antibiotic resistance that is occurring worldwide. In the current research, short amphiphilic antibacterial and antibiofilm agents were produced by tuning the hydrophobic and cationic groups of anthranilamide peptidomimetics. The attachment of a lysine cationic group at the tail position increased activity against E. coli by >16-fold (from >125 μM to 15.6 μM) and greatly reduced cytotoxicity against mammalian cells (from ≤20 μM to ≥150 μM). These compounds showed significant disruption of preformed biofilms of S. aureus at micromolar concentrations