The break quantity rule in a 1-warehouse, N-retailers distribution system

In this paper the effect of the break quantity rule on the inventory costs in a 1-warehouse, N-retailers distribution system is analyzed. The break quantity rule is to deliver large orders from the warehouse, and small orders from the nearest retailer, where a so--called break quantity determines whether an order is small or large. Under the assumptions that the stock at the warehouse can only be used to satisfy large orders, and that demand during the leadtimes is normally distributed, an expression for the inventory costs is derived. The objective of this paper is to provide insight into the effect of the break quantity rule on the inventory holding costs, and therefore we present extensive computational results, showing that in many cases the rule leads to a significant cost reduction

On the newsboy model with a cutoff transaction size

In this paper we analyse the effect of satisfying in a different way customers with an order larger than a prespecified cutoff transaction size, in a simple newsboy setting. For compound Poisson demand with discrete order sizes, we show how to determine the expected costs and the optimal cutoff transaction size. Moreover, by approximating the distribution of the total demand during a period by the normal distribution one can determine an expression for the average cost function that depends on the cutoff transaction size only. A main advantage of this approximation is that the computational effort is much less. The quality of using the normal approximation is evaluated through a number of numerical experiments, which show that the approximative results are satisfactory

Shaping the BRCAness mutational landscape by alternative double-strand break repair, replication stress and mitotic aberrancies

Tumours with mutations in the BRCA1/BRCA2 genes have impaired double-stranded DNA break repair, compromised replication fork protection and increased sensitivity to replication blocking agents, a phenotype collectively known as 'BRCAness'. Tumours with a BRCAness phenotype become dependent on alternative repair pathways that are error-prone and introduce specific patterns of somatic mutations across the genome. The increasing availability of next-generation sequencing data of tumour samples has enabled identification of distinct mutational signatures associated with BRCAness. These signatures reveal that alternative repair pathways, including Polymerase θ-mediated alternative end-joining and RAD52-mediated single strand annealing are active in BRCA1/2-deficient tumours, pointing towards potential therapeutic targets in these tumours. Additionally, insight into the mutations and consequences of unrepaired DNA lesions may also aid in the identification of BRCA-like tumours lacking BRCA1/BRCA2 gene inactivation. This is clinically relevant, as these tumours respond favourably to treatment with DNA-damaging agents, including PARP inhibitors or cisplatin, which have been successfully used to treat patients with BRCA1/2-defective tumours. In this review, we aim to provide insight in the origins of the mutational landscape associated with BRCAness by exploring the molecular biology of alternative DNA repair pathways, which may represent actionable therapeutic targets in in these cells

Typology of coastal urban vulnerability under rapid urbanization

Coastal areas are urbanizing at unprecedented rates, particularly in low- and middle-income countries. Combinations of long-standing and emerging problems in these urban areas generate vulnerability for human well-being and ecosystems alike. This baseline study provides a spatially explicit global systematization of these problems into typical urban vulnerability profiles for the year 2000 using largely sub-national data. Using 11 indicator datasets for urban expansion, urban population growth, marginalization of poor populations, government effectiveness, exposures and damages to climate-related extreme events, low-lying settlement, and wetlands prevalence, a cluster analysis reveals a global typology of seven clearly distinguishable clusters, or urban profiles of vulnerability. Each profile is characterized by a specific data-value combination of indicators representing mechanisms that generate vulnerability. Using 21 studies for testing the plausibility, we identify seven key profile-based vulnerabilities for urban populations, which are relevant in the context of global urbanization, expansion, and climate change. We show which urban coasts are similar in this regard. Sensitivity and exposure to extreme climate-related events, and government effectiveness, are the most important factors for the huge asymmetries of vulnerability between profiles. Against the background of underlying global trends we propose entry points for profile-based vulnerability reduction. The study provides a baseline for further pattern analysis in the rapidly urbanizing coastal fringe as data availability increases. We propose to explore socio-ecologically similar coastal urban areas as a basis for sharing experience and vulnerability-reducing measures among them

On the use of break quantities in multi--echelon distribution systems

In multi-echelon distribution systems it is usually assumed that demand is only satisfied from the lowest echelon. In this paper we will consider the case where demand can be satisfied from any level in the system. However, then the problem arises of how to allocate orders from customers to the different locations. A possible way of dealing with this problem consists of using a so-called break quantity rule. This easy implementable rule is to deliver every order with a size exceeding the break quantity from a higher echelon. The use of the break quantity rule now results in a reduction of the demand variability at the retailer and hence less safety stocks need to be held. The concept is studied for a two-echelon distribution system, consisting of one warehouse and one retailer, where the inventory at the retailer is controlled by an order up to level policy, and where at the warehouse there is enough inventory to satisfy all orders from the retailer and the customers. For this system an approximation for the long run average costs as a function of the break quantity is derived, and an algorithm is presented to determine the cost-optimal break quantity. Computational results indicate that the break quantity rule can lead to significant cost reductions

PPM1D activity promotes the replication stress caused by cyclin E1 overexpression

Oncogene-induced replication stress has been recognized as a major cause of genome instability in cancer cells. Increased expression of cyclin E1 caused by amplification of the CCNE1 gene is a common cause of replication stress in various cancers. Protein phosphatase magnesium-dependent 1 delta (PPM1D) is a negative regulator of p53 and has been implicated in termination of the cell cycle checkpoint. Amplification of the PPM1D gene or frameshift mutations in its final exon promote tumorigenesis. Here, we show that PPM1D activity further increases the replication stress caused by overexpression of cyclin E1. In particular, we demonstrate that cells expressing a truncated mutant of PPM1D progress faster from G1 to S phase and fail to complete licensing of the replication origins. In addition, we show that transcription-replication collisions and replication fork slowing caused by CCNE1 overexpression are exaggerated in cells expressing the truncated PPM1D. Finally, replication speed as well as accumulation of focal DNA copy number alterations caused by induction of CCNE1 expression was rescued by pharmacological inhibition of PPM1D. We propose that increased activity of PPM1D suppresses the checkpoint function of p53 and thus promotes genome instability in cells expressing the CCNE1 oncogene

Identification of conformational epitopes for human IgG on Chemotaxis inhibitory protein of Staphylococcus aureus

<p>Abstract</p> <p>Background</p> <p>The Chemotaxis inhibitory protein of <it>Staphylococcus aureus </it>(CHIPS) blocks the Complement fragment C5a receptor (C5aR) and formylated peptide receptor (FPR) and is thereby a potent inhibitor of neutrophil chemotaxis and activation of inflammatory responses. The majority of the healthy human population has antibodies against CHIPS that have been shown to interfere with its function <it>in vitro</it>. The aim of this study was to define potential epitopes for human antibodies on the CHIPS surface. We also initiate the process to identify a mutated CHIPS molecule that is not efficiently recognized by preformed anti-CHIPS antibodies and retains anti-inflammatory activity.</p> <p>Results</p> <p>In this paper, we panned peptide displaying phage libraries against a pool of CHIPS specific affinity-purified polyclonal human IgG. The selected peptides could be divided into two groups of sequences. The first group was the most dominant with 36 of the 48 sequenced clones represented. Binding to human affinity-purified IgG was verified by ELISA for a selection of peptide sequences in phage format. For further analysis, one peptide was chemically synthesized and antibodies affinity-purified on this peptide were found to bind the CHIPS molecule as studied by ELISA and Surface Plasmon Resonance. Furthermore, seven potential conformational epitopes responsible for antibody recognition were identified by mapping phage selected peptide sequences on the CHIPS surface as defined in the NMR structure of the recombinant CHIPS_31–121protein. Mapped epitopes were verified by <it>in vitro </it>mutational analysis of the CHIPS molecule. Single mutations introduced in the proposed antibody epitopes were shown to decrease antibody binding to CHIPS. The biological function in terms of C5aR signaling was studied by flow cytometry. A few mutations were shown to affect this biological function as well as the antibody binding.</p> <p>Conclusion</p> <p>Conformational epitopes recognized by human antibodies have been mapped on the CHIPS surface and amino acid residues involved in both antibody and C5aR interaction could be defined. This information has implications for the development of an effective anti-inflammatory agent based on a functional CHIPS molecule with low interaction with human IgG.</p

Sound Level Monitoring at Live Events, Part 1–Live Dynamic Range

Musical dynamics are often central within pieces of music and are therefore likely to be fundamental to the live event listening experience. While metrics exist in broadcasting and recording to quantify dynamics, such measures work on high-resolution data. Live event sound level monitoring data is typically low-resolution (logged at one second intervals or less), which necessitates bespoke musical dynamics quantification. Live dynamic range (LDR) is presented and validated here to serve this purpose, where measurement data is conditioned to remove song breaks and sound level regulation-imposed adjustments to extract the true musical dynamics from a live performance. Results show consistent objective performance of the algorithm, as tested on synthetic data as well as datasets from previous performances.N/