File and Object Replication in Data Grids

Data replication is a key issue in a Data Grid and can be managed in different ways and at different levels of granularity: for example, at the file level or object level. In the High Energy Physics community, Data Grids are being developed to support the distributed analysis of experimental data. We have produced a prototype data replication tool, the Grid Data Mirroring Package (GDMP) that is in production use in one physics experiment, with middleware provided by the Globus Toolkit used for authentication, data movement, and other purposes. We present here a new, enhanced GDMP architecture and prototype implementation that uses Globus Data Grid tools for efficient file replication. We also explain how this architecture can address object replication issues in an object-oriented database management system. File transfer over wide-area networks requires specific performance tuning in order to gain optimal data transfer rates. We present performance results obtained with GridFTP, an enhanced version of FTP, and discuss tuning parameters.     

Structural/mechanistic insights into the efficacy of nonclassical β‐lactamase inhibitors against extensively drug resistant Stenotrophomonas maltophilia clinical isolates

Clavulanic acid and avibactam are clinically deployed serine β‐lactamase inhibitors, important as a defence against antibacterial resistance. Bicyclic boronates are recently discovered inhibitors of serine and some metallo β‐lactamases. Here, we show that avibactam and a bicyclic boronate inhibit L2 (serine β‐lactamase) but not L1 (metallo β‐lactamase) from the extensively drug resistant human pathogen Stenotrophomonas maltophilia. X‐ray crystallography revealed that both inhibitors bind L2 by covalent attachment to the nucleophilic serine. Both inhibitors reverse ceftazidime resistance in S. maltophilia because, unlike clavulanic acid, they do not induce L1 production. Ceftazidime/inhibitor resistant mutants hyperproduce L1, but retain aztreonam/inhibitor susceptibility because aztreonam is not an L1 substrate. Importantly, avibactam, but not the bicyclic boronate is deactivated by L1 at a low rate; the utility of avibactam might be compromised by mutations that increase this deactivation rate. These data rationalize the observed clinical efficacy of ceftazidime/avibactam plus aztreonam as combination therapy for S. maltophilia infections and confirm that aztreonam‐like β‐lactams plus nonclassical β‐lactamase inhibitors, particularly avibactam‐like and bicyclic boronate compounds, have potential for treating infections caused by this most intractable of drug resistant pathogens.     

Prophylactic effects of ellagic acid and rosmarinic acid on doxorubicin‐induced neurotoxicity in rats

Doxorubicin (DOX) is a chemotherapeutic agent widely used in human malignancies. Its long‐term use cause neurobiological side effects. The aim of the present study was to investigate the prophylactic effect exerted by daily administration of ellagic acid (EA) and rosmarinic acid (RA) on DOX‐induced neurotoxicity in rats. Our data showed that DOX‐induced significant elevation of brain malondialdehyde, tumor necrosis factor‐alpha (TNF‐α), inducible nitric oxide synthase (iNOS), caspase‐3, and cholinesterase associated with significant reduction in reduced glutathione, monoamines namely serotonin, dopamine, as well as norepinephrine. Concomitant administration of EA (10 mg/kg/day, p.o. for 14 days) and/or RA (75 mg/kg/day, p.o. for 14 days) with DOX significantly mitigated the neural changes induced by DOX. Meanwhile, treatment ameliorated pro‐inflammatory cytokines as TNF‐α, iNOS, and attenuated oxidative stress biomarkers as well as brain monoamines. In conclusion, EA and RA can effectively protect against DOX‐induced neurotoxicity, and the mechanisms underlying the neuroprotective effect are potentially associated with its antioxidant, anti‐inflammatory, and antiapoptotic properties.     

Protocols and pitfalls in obtaining fatty acid-binding proteins for biophysical studies of ligand-protein and protein-protein interactions

Adipocyte fatty acid-binding protein (AFABP: FABP4) is a member of the intracellular lipid-binding protein family that is thought to target long-chain fatty acids to nuclear receptors such as peroxisome proliferator-activated receptor gamma (PPARγ), which in turn plays roles in insulin resistance and obesity. A molecular understanding of AFABP function requires robust isolation of the protein in liganded and free forms as well as characterization of its oligomerization state(s) under physiological conditions. We report development of a protocol to optimize the production of members of this protein family in pure form, including removal of their bound lipids by mixing with hydrophobically functionalized hydroxypropyl dextran beads and validation by two-dimensional NMR spectroscopy. The formation of self-associated or covalently bonded protein dimers was evaluated critically using gel filtration chromatography, revealing conditions that promote or prevent formation of disulfide-linked homodimers. The resulting scheme provides a solid foundation for future investigations of AFABP interactions with key ligand and protein partners involved in lipid metabolism.     

Biochemical characterization of N-methyl N’-nitro-N-nitrosoguanidine-induced cadmium resistant mutants ofAspergillus niger

Two cadmium resistant mutants (Cd₁ and Cd₂) ofAspergillus niger, among the six isolated by mutagenization with N-methyl N’-nitro-N-nitrosoguanidine (MNNG) at pH 6.4 were selected for the study. Analysis of lipid composition of the mutants and the wildtype indicated that total lipid as well as individual lipids of the cadmium resistant mutants were changed as compared with that of the wildtype. The increased activities of metal-lothionein and reduced activities of D-xylose isomerase and L-phenylalanine ammonia lyase in cell free extract of the cadmium resistant mutants suggested that mutants could allow high concentration of cadmium salt as compared with that of the wildtype. The respiratory activity and intracellular as well as extracellular Cd²⁺ concentration of the mutants reflected the high tolerance of the Cd mutants to cadmium ion.     

Cardiac and renal effects of omapatrilat, a vasopeptidase inhibitor, in rats with experimental congestive heart failure

Omapatrilat (OMP) is a novel mixed inhibitor of angiotensin-converting enzyme (ACE) and neutral endopeptidase 24.11 (NEP), the enzyme that metabolizes natriuretic peptides. Congestive heart failure (CHF) is characterized by excessive sodium retention, attributed to both an excessive effect of angiotensin II and diminished responsiveness to natriuretic peptides. In this study, we examined the acute and chronic renal and cardiac effects of OMP in rats with compensated [urinary sodium excretion (UNaV) > 1,200 microeq/day] and decompensated (UNaV < 100 microeq/day) CHF, induced by a surgical aortocaval fistula (ACF). Bolus injection of OMP (10 mg/kg) to sham controls produced significant diuretic and natriuretic responses [UNaV increased from 0.67 +/- 0.19 to 3.27 +/- 1.35 microeq/min, P < 0.05; fractional sodium excretion (FENa) increased from 0.23 +/- 0.06 to 0.95 +/- 0.34%, P < 0.01] despite a significant decline in blood pressure (BP). Rats with compensated CHF displayed blunted diuresis and natriuresis to this dose of OMP but a significant decrease in BP. However, in rats with decompensated CHF, OMP induced significant natriuresis (FENa increased from 0.18 +/- 0.15 to 0.82 +/- 0.26%, P < 0.05) despite a further decrease in BP (from 90 +/- 9 to 71 +/- 6 mmHg, P < 0.01). Two weeks after ACF, the heart/body weight ratio was significantly greater in rats with CHF than controls (0.51 +/- 0.026 vs. 0.30 +/- 0.004%, P < 0.0001), and UNaV was significantly lower. Immediate or late (1 or 6 days after ACF) OMP treatment in the drinking water (140 mg/l) reduced cardiac hypertrophy to 0.41-0.43% (P < 0.01) and induced natriuresis. These results suggest that OMP improves both sodium balance and cardiac remodeling and might be advantageous to ACE inhibitors for the treatment of decompensated CHF.     

Chromosome dynamics: actin's gone fishing

Chromosome congression and segregation have been widely known to be coordinated by the function of the dynamic spindle microtubules. But recent work suggests that oocytes may employ a unique actin-dependent mechanism of chromosome delivery to the spindle.     

Lower eyelid blepharoplasty: analysis of indications and the treatment of 100 patients

Traditionally, lower lid blepharoplasty has been confined to a choice of skin or skin-muscle flap transcutaneous blepharoplasty. In the past decade, in particular, various new techniques and technologies have emerged, altering our ability to treat the lower eyelids. These techniques include transconjunctival blepharoplasty, a variety of canthopexy procedures, fat-conserving or fat-replacing methods, wedge excision, and laser resurfacing techniques, and they allow a more individualized approach based on variations in anatomical features and patient goals. A retrospective review of data for 100 consecutive patients (ranging in age from 30 to 80 years) who underwent lower eyelid procedures during a 12-month period is presented. Procedures were categorized as follows: lower lid blepharoplasty, 35 cases; lower lid transconjunctival blepharoplasty, 27 cases; lower lid transconjunctival blepharoplasty with laser resurfacing, 17 cases; lower lid laser resurfacing, 16 cases; tarsorrhaphy with lower lid operation, three cases; tarsorrhaphy with laser resurfacing, two cases. Two complications of retained fat pads (one medial and one lateral) were encountered and were addressed with a secondary operation using a transconjunctival blepharoplasty approach. The results indicate that laser treatment has become the predominant form of lower eyelid resurfacing and that transconjunctival blepharoplasty is now the most common surgical procedure for the lower eyelid. All of our tarsorrhaphy procedures were performed for patients who had previously undergone surgical treatment of the lower eyelids. An algorithm based on physical findings and these techniques has been developed, for appropriate tailoring of the procedure to each patient's specific concerns. With the availability of a variety of techniques, an individualized approach based on variations in anatomical features is feasible.     

Evidence for time-dependent maximum increase of free radical damage and eicosanoid formation in the brain as related to duration of cardiac arrest and cardio-pulmonary resuscitation

Recovery of neurological function in patients following cardiac arrest and cardiopulmonary resuscitation (CPR) is a complex event. Free radical induced oxidative stress is supposed to be involved in this process. We studied levels of 8-iso-PGF2alpha (indicating oxidative injury) and 15-keto-dihydro-PGF2alpha (indicating inflammatory response) in venous plasma obtained from the jugular bulb in a porcine model of experimental cardiopulmonary resuscitation (CPR) where 2, 5, 8, 10 or 12 min of ventricular fibrillation (VF) was followed by 5 or 8 min of closed-chest CPR. A significant increase of 8-iso-PGF2alpha was observed immediately following restoration of spontaneous circulation in all experiments of various duration of VF and CPR. No such increase was seen in a control group. When compared between the groups there was a duration-dependent maximum increase of 8-iso-PGF2alpha which was greatest in animals subjected to the longest period (VF12 min + CPR8 min) of no or low blood flow. In contrast, the greatest increase of 15-keto-dihydro-PGF2alpha was observed in the 13 min group (VF8 min + CPR5 min). Thus, a time-dependent cerebral oxidative injury occurs in conjunction which cardiac arrest and CPR.