A comparative study of FMS tool allocation and part type selection approaches for a varying part type mix

Hankins and Rovito (1984) examined the impact of different tool policies on cutting tool inventory levels and spindle utilization for a flexible manufacturing system (FMS). This study provides a broader perspective of the impact of tool allocation approaches on flow times, tardiness, percent of orders tardy, machine utilization, and robot utilization. Part type selection procedures have been suggested for the FMS prerelease planning problem. However, very little research has specifically evaluated the part type selection procedures across different tool allocation approaches. Also, with the exception of Stecke and Kim (1988, 1991) no other known study has provided any insights on what tool allocation approaches are appropriate when processing different mixes of part types. This research is devoted to addressing those issues. Three tool allocation approaches, three production scheduling rules, and three levels of part mix are evaluated in this study through a similation model of a flexible manufacturing system. The specific impacts of the tool approaches, their interaction effects with the part type selection rules, and their effectiveness at different part type mix levels are provided through the use of a regression metamodel.     

Tau Kinetics in Neurons and the Human Central Nervous System

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Cu(II) organizes beta-2-microglobulin oligomers but is released upon amyloid formation

beta-2-Microglobulin (beta2m) is deposited as amyloid fibrils in the bones and joints of patients undergoing long-term dialysis treatment as a result of kidney failure. Previous work has shown that biologically relevant amounts of Cu(II) can cause beta2m to be converted to amyloid fibrils under physiological conditions in vitro. In this work, dynamic light scattering, mass spectrometry, and size-exclusion chromatography are used to characterize the role that Cu plays in the formation of oligomeric intermediates that precede fibril formation. Cu(II) is found to be necessary for the stability of the dimer and an initial form of the tetramer. The initially formed tetramer then undergoes a structural change to a state that no longer binds Cu(II) before progressing to a hexameric state. Based on these results, we propose that the lag phase associated with beta2m fibril formation is partially accounted for by the structural transition of the tetramer that results in Cu(II) loss. Consistent with this observation is the determination that the mature beta2m amyloid fibrils do not contain Cu. Thus, Cu(II) appears to play a catalytic role by enabling the organization of the necessary oligomeric intermediates that precede beta2m amyloid formation.     

Reasons for Missing Antiretroviral Therapy: Results from a Multi-Country Study in Tanzania,Uganda, and Zambia

Objectives

To identify the reasons patients miss taking their antiretroviral therapy (ART) and the proportion who miss their ART because of symptoms; and to explore the association between symptoms and incomplete adherence.

Methods

Secondary analysis of data collected during a cross-sectional study that examined ART adherence among adults from 18 purposefully selected sites in Tanzania, Uganda, and Zambia. We interviewed 250 systematically selected patients per facility (≥18 years) on reasons for missing ART and symptoms they had experienced (using the HIV Symptom Index). We abstracted clinical data from the patients’ medical, pharmacy, and laboratory records. Incomplete adherence was defined as having missed ART for at least 48 consecutive hours during the past 3 months.

Results

Twenty-nine percent of participants reported at least one reason for having ever missed ART (1278/4425). The most frequent reason was simply forgetting (681/1278 or 53%), followed by ART-related hunger or not having enough food (30%), and symptoms (12%). The median number of symptoms reported by participants was 4 (IQR: 2–7). Every additional symptom increased the odds of incomplete adherence by 12% (OR: 1.1, 95% CI: 1.1–1.2). Female participants and participants initiated on a regimen containing stavudine were more likely to report greater numbers of symptoms.

Conclusions

Symptoms were a common reason for missing ART, together with simply forgetting and food insecurity. A combination of ART regimens with fewer side effects, use of mobile phone text message reminders, and integration of food supplementation and livelihood programmes into HIV programmes, have the potential to decrease missed ART and hence to improve adherence and the outcomes of ART programmes.     

Empirical studies of escape behavior find mixed support for the race for life model

Escape theory has been exceptionally successful in conceptualizing and accurately predicting effects of numerous factors that affect predation risk and explaining variation in flight initiation distance (FID; predator–prey distance when escape begins). Less explored is the relative orientation of an approaching predator, prey, and its eventual refuge. The relationship between an approaching threat and its refuge can be expressed as an angle we call the “interpath angle” or “Φ,” which describes the angle between the paths of predator and prey to the prey’s refuge and thus expresses the degree to which prey must run toward an approaching predator. In general, we might expect that prey would escape at greater distances if they must flee toward a predator to reach its burrow. The “race for life” model makes formal predictions about how Φ should affect FID. We evaluated the model by studying escape decisions in yellow-bellied marmots Marmota flaviventer, a species which flees to burrows. We found support for some of the model’s predictions, yet the relationship between Φ and FID was less clear. Marmots may not assess Φ in a continuous fashion; but we found that binning angle into 4 45° bins explained a similar amount of variation as models that analyzed angle continuously. Future studies of Φ, especially those that focus on how different species perceive relative orientation, will likely enhance our understanding of its importance in flight decisions.     

Caenorhabditis elegans,a pluricellular model organism to screen new genes involved in mitochondrial genome maintenance

The inheritance of functional mitochondria depends on faithful replication and transmission of mitochondrial DNA (mtDNA). A large and heterogeneous group of human disorders is associated with mitochondrial genome quantitative and qualitative anomalies. Several nuclear genes have been shown to account for these severe OXPHOS disorders. However, in several cases, the disease-causing mutations still remain unknown.Caenorhabditis elegans has been largely used for studying various biological functions because this multicellular organism has short life cycle and is easy to grow in the laboratory. Mitochondrial functions are relatively well conserved between human and C. elegans, and heteroplasmy exists in this organism as in human. C. elegans therefore represents a useful tool for studying mtDNA maintenance. Suppression by RNA interference of genes involved in mtDNA replication such as polg-1, encoding the mitochondrial DNA polymerase, results in reduced mtDNA copy number but in a normal phenotype of the F1 worms. By combining RNAi of genes involved in mtDNA maintenance and EtBr exposure, we were able to reveal a strong and specific phenotype (developmental larval arrest) associated to a severe decrease of mtDNA copy number. Moreover, we tested and validated the screen efficiency for human orthologous genes encoding mitochondrial nucleoid proteins. This allowed us to identify several genes that seem to be closely related to mtDNA maintenance in C. elegans.This work reports a first step in the further development of a large-scale screening in C. elegans that should allow to identify new genes of mtDNA maintenance whose human orthologs will obviously constitute new candidate genes for patients with quantitative or qualitative mtDNA anomalies.     

Preparation of 2,3′-Anhydropyrimidine Nucleosides using N,N-Diethylaminosulfur Trifluoride (DAST)

Abstract

2,3′-Anhydro-2′-deoxy-5′-0-(triphenyl methyl) and 5′-0-(monomethoxytriphenylmethyl) pyrimidine nucleosides of uracil, thymine, and cytosine were synthesized in a single step from their 2′-deoxy-5′-0-(triphenylmethyl) or 5′-0-(monomethoxytriphenylmethyl) precursors using N,N-diethylaminosulfur trifluoride (DAST). The anhydronucleosides were either isolated or directly converted to their respective 2-deoxy-β-D-threo-pentofuranosyl nucleosides using sodium hydroxide in ethanol.     

A novel strategy for development of recombinant antitoxin therapeutics tested in a mouse botulism model

Antitoxins are needed that can be produced economically with improved safety and shelf life compared to conventional antisera-based therapeutics. Here we report a practical strategy for development of simple antitoxin therapeutics with substantial advantages over currently available treatments. The therapeutic strategy employs a single recombinant 'targeting agent' that binds a toxin at two unique sites and a 'clearing Ab' that binds two epitopes present on each targeting agent. Co-administration of the targeting agent and the clearing Ab results in decoration of the toxin with up to four Abs to promote accelerated clearance. The therapeutic strategy was applied to two Botulinum neurotoxin (BoNT) serotypes and protected mice from lethality in two different intoxication models with an efficacy equivalent to conventional antitoxin serum. Targeting agents were a single recombinant protein consisting of a heterodimer of two camelid anti-BoNT heavy-chain-only Ab V(H) (VHH) binding domains and two E-tag epitopes. The clearing mAb was an anti-E-tag mAb. By comparing the in vivo efficacy of treatments that employed neutralizing vs. non-neutralizing agents or the presence vs. absence of clearing Ab permitted unprecedented insight into the roles of toxin neutralization and clearance in antitoxin efficacy. Surprisingly, when a post-intoxication treatment model was used, a toxin-neutralizing heterodimer agent fully protected mice from intoxication even in the absence of clearing Ab. Thus a single, easy-to-produce recombinant protein was as efficacious as polyclonal antiserum in a clinically-relevant mouse model of botulism. This strategy should have widespread application in antitoxin development and other therapies in which neutralization and/or accelerated clearance of a serum biomolecule can offer therapeutic benefit.     

Quiescin sulfhydryl oxidase 1 promotes invasion of pancreatic tumor cells mediated by matrix metalloproteinases

Quiescin sulfhydryl oxidase 1 (QSOX1) oxidizes sulfhydryl groups to form disulfide bonds in proteins. We previously mapped a peptide in plasma from pancreatic ductal adenocarcinoma (PDA) patients back to an overexpressed QSOX1 parent protein. In addition to overexpression in pancreatic cancer cell lines, 29 of 37 patients diagnosed with PDA expressed QSOX1 protein in tumor cells, but QSOX1 was not detected in normal adjacent tissues or in a transformed, but nontumorigenic cell line. To begin to evaluate the advantage QSOX1 might provide to tumors, we suppressed QSOX1 protein expression using short hairpin (sh) RNA in two pancreatic cancer cell lines. Growth, cell cycle, apoptosis, invasion, and matrix metalloproteinase (MMP) activity were evaluated. QSOX1 shRNA suppressed both short and long isoforms of the protein, showing a significant effect on cell growth, cell cycle, and apoptosis. However, QSOX1 shRNA dramatically inhibited the abilities of BxPC-3 and Panc-1 pancreatic tumor cells to invade through Matrigel in a modified Boyden chamber assay. Mechanistically, gelatin zymography indicated that QSOX1 plays an important role in activation of MMP-2 and MMP-9. Taken together, our results suggest that the mechanism of QSOX1-mediated tumor cell invasion is by activation of MMP-2 and MMP-9.     

Implementing and Measuring the Level of Laboratory Service Integration in a Program Setting in Nigeria

Background

The surge of donor funds to fight HIV&AIDS epidemic inadvertently resulted in the setup of laboratories as parallel structures to rapidly respond to the identified need. However these parallel structures are a threat to the existing fragile laboratory systems. Laboratory service integration is critical to remedy this situation. This paper describes an approach to quantitatively measure and track integration of HIV-related laboratory services into the mainstream laboratory services and highlight some key intervention steps taken, to enhance service integration.

Method

A quantitative before-and-after study conducted in 122 Family Health International (FHI360) supported health facilities across Nigeria. A minimum service package was identified including management structure; trainings; equipment utilization and maintenance; information, commodity and quality management for laboratory integration. A check list was used to assess facilities at baseline and 3 months follow-up. Level of integration was assessed on an ordinal scale (0 = no integration, 1 = partial integration, 2 = full integration) for each service package. A composite score grading expressed as a percentage of total obtainable score of 14 was defined and used to classify facilities (≤80% FULL, 25% to 79% PARTIAL and <25% NO integration). Weaknesses were noted and addressed.

Results

We analyzed 9 (7.4%) primary, 104 (85.2%) secondary and 9 (7.4%) tertiary level facilities. There were statistically significant differences in integration levels between baseline and 3 months follow-up period (p<0.01). Baseline median total integration score was 4 (IQR 3 to 5) compared to 7 (IQR 4 to 9) at 3 months follow-up (p = 0.000). Partial and fully integrated laboratory systems were 64 (52.5%) and 0 (0.0%) at baseline, compared to 100 (82.0%) and 3 (2.4%) respectively at 3 months follow-up (p = 0.000).

Discussion

This project showcases our novel approach to measure the status of each laboratory on the integration continuum.