Differential effects of myeloperoxidase-derived oxidants on Escherichia coli DNA replication

The microbicidal myeloperoxidase (MPO)-H2O2-chloride system strongly inhibits Escherichia coli DNA synthesis. Also, cell envelopes from MPO-treated E. coli cells lose their ability to interact with hemimethylated DNA sequences of oriC, the chromosomal origin of replication, raising the prospect that suppression of DNA synthesis involves impairment of oriC-related functions (H. Rosen, et al. Proc. Natl. Acad. Sci. USA, 87:10048-10052, 1990). To evaluate whether origin-specific DNA sequences play a role in the MPO effect on E. coli DNA synthesis, plasmid DNA replication was compared to total (chromosomal) DNA replication for six plasmids with three distinct origins of replication. Plasmid pCM700 replication, replicating from oriC, was as sensitive to MPO-mediated inhibition as was total (chromosomal) DNA replication. A regression line describing this relationship had a slope of 0.90, and the r2 was 0.89. In contrast, the replication activities of three of four non-oriC plasmids, pUC19, pACYC184, and pSC101, demonstrated significant early resistance to inhibition by MPO-derived oxidants. The exception to this resistance pattern was plasmid pSP102, which has an origin derived from P1 phage. pSP102 replication declined similarly to that of total DNA synthesis. The regression line for pSP102 replication versus total DNA synthesis had a slope of 0.95, and the r2 was 0.92. The biochemical requirements for P1-mediated replication are strikingly similar to those for oriC-mediated replication. It is proposed that one of these requirements, common to oriC and the P1 origin but not critical to the replication of the other non-oriC plasmids, is an important target for MPO-mediated oxidations that mediate the initial decline in E. coli chromosomal DNA synthesis.     

Effects of 42 hr of total sleep deprivation on component processes of verbal working memory.

The current investigation examined changes in working memory (WM) component processes following total sleep deprivation (TSD) in a sample of healthy young persons. Forty subjects were administered a verbal form of a continuous recognition test (CRT) before and after 42 hr of TSD. Parameters of a computational model of the CRT reflecting attention, WM span, and rate of episodic memory encoding were estimated for each individual. Subjects made more errors on the test following sleep deprivation. Analysis of model parameters revealed statistically independent declines in both the attention and WM span parameters, with a larger effect observed for the decline in WM span. Examination of individual profiles suggested that the effects of TSD on verbal WM component processes vary from person to person. Declines in global verbal WM functioning appear to be primarily driven by reduced WM span and attention; however, these effects may be individual-specific. Further applications of the computational model for examining WM component processes with sleep deprivation and other clinical populations are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Pathophysiology of chronic obstructive pulmonary disease

The prevalence of COPD has increased as mortality from the two organ systems affected by the same risk factors of smoking, heart attacks and strokes, has decreased. Once diagnosed, COPD is progressive and may lead to disability, usually due to dyspnea, at a relatively early age (60 to 80 years of age). COPD is usually caused by destruction of the lung parenchyma or by disease affecting the airways. In most patients both processes exist simultaneously. Less often recognized is the fact that the disease does not affect all portions of the lung alike, which causes different physiologic behaviors in different parts of the lung. This article integrates the pathologic changes of COPD with the known adaptive and maladaptive consequences of those changes. An understanding of these changes should result in an increased capacity to comprehend the different therapeutic strategies that have been developed to decrease the symptoms and improve the well-being of patients with COPD.     

Stochastic and Dynamic Shipper Carrier Network Design Problem

The focus of this work is to determine the optimal storage capacity to be installed on transhipment nodes by shippers in a dynamic shipper carrier network under stochastic demand. A two stage linear program with recourse formulation is developed where in the first stage, the shipper decides the optimal capacity to be installed on transhipment nodes. In the second stage, the shipper chooses a routing strategy based on the realized demand. The performance of the following solution methods: Stochastic L Shaped Method, Regularized Decomposition and L Shaped Method with preliminary cuts were compared for various network sizes and numerous demand scenarios. A novel capacity shifting heuristic was introduced to generate a feasible implementable solution which significantly improves the performance of Regularized Decomposition and provides the best performance in the cases tested. Various ways of generating analytical bounds on the objective function value was discussed. The new capacity shifting heuristic was found to be efficient in generating tight upper bounds. Even though the formulation considered in this paper is for a single commodity, the model can be easily extended to account for multiple commodities.     

Development of novel, potent, and selective dopamine reuptake inhibitors through alteration of the piperazine ring of 1-[2-(diphenylmethoxy)ethyl]-and 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazines (GBR 12935 and GBR 12909)

The design, synthesis, and biological evaluation of compounds related to the dopamine (DA) uptake inhibitors: 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine (1) and 1-[2-[bis-(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (2) (GBR 12395 and GBR 12909, respectively), directed toward the development and identification of new ligands interacting with high potency and selectivity at the dopamine transporter (DAT) is reported. The substitution of the piperazine ring in the GBR structure with other diamine moieties resulted in the retention of the high affinity of new ligands for the DAT. Some of the modified GBR analogs (e.g. 8, 10, (-)-49, or (-)-50) displayed substantially higher selectivity (4736- to 693-fold) for the dopamine (DA) versus the serotonin (5HT) reuptake site than the parent compounds. The bis(p-fluoro) substitution in the (diphenylmethoxy)ethyl fragment slightly increased the affinity of the ligands at the DA reuptake site but reduced their selectivity at this site (e.g. 9 and 8, 11 and 10, or 17 and 16, respectively). Congeners, such as the series of monosubstituted and symmetrically disubstituted piperazines and trans-2,5-dimethylpiperazines, which lack the (diphenylmethoxy)ethyl substituent lost the affinity for the DAT yet exhibited very high potency for binding to the sigma receptors (e.g.28). The chiral pyrrolidine derivatives of 1, (-)-49, and (+)-49, exhibited an enantioselectivity ratio of 181 and 146 for the inhibition of DA reuptake and binding to the DAT, respectively.