The Top-Dog Index: A New Measurement for the Demand Consistency of the Size Distribution in Pre-Pack Orders for a Fashion Discounter with Many Small Branches

We propose the new Top-Dog-Index, a measure for the branch-dependent historic deviation of the supply data of apparel sizes from the sales data of a fashion discounter. A common approach is to estimate demand for sizes directly from the sales data. This approach may yield information for the demand for sizes if aggregated over all branches and products. However, as we will show in a real-world business case, this direct approach is in general not capable to provide information about each branch's individual demand for sizes: the supply per branch is so small that either the number of sales is statistically too small for a good estimate (early measurement) or there will be too much unsatisfied demand neglected in the sales data (late measurement). Moreover, in our real-world data we could not verify any of the demand distribution assumptions suggested in the literature. Our approach cannot estimate the demand for sizes directly. It can, however, individually measure for each branch the scarcest and the amplest sizes, aggregated over all products. This measurement can iteratively be used to adapt the size distributions in the pre-pack orders for the future. A real-world blind study shows the potential of this distribution free heuristic optimization approach: The gross yield measured in percent of gross value was almost one percentage point higher in the test-group branches than in the control-group branches.Comment: 22 pages, 15 figure

Recent Change—North Sea

This chapter discusses past and ongoing change in the following physical variables within the North Sea: temperature, salinity and stratification; currents and circulation; mean sea level; and extreme sea levels. Also considered are carbon dioxide; pH and nutrients; oxygen; suspended particulate matter and turbidity; coastal erosion, sedimentation and morphology; and sea ice. The distinctive character of the Wadden Sea is addressed, with a particular focus on nutrients and sediments. This chapter covers the past 200 years and focuses on the historical development of evidence (measurements, process understanding and models), the form, duration and accuracy of the evidence available, and what the evidence shows in terms of the state and trends in the respective variables. Much work has focused on detecting long-term change in the North Sea region, either from measurements or with models. Attempts to attribute such changes to, for example, anthropogenic forcing are still missing for the North Sea. Studies are urgently needed to assess consistency between observed changes and current expectations, in order to increase the level of confidence in projections of expected future conditions

Modeling inflammation and oxidative stress in gastrointestinal disease development using novel organotypic culture systems

Gastroesophageal reflux disease (GERD), Barrett's esophagus (BE), graft-versus-host disease (GVHD), and inflammatory bowel diseases such as ulcerative colitis and Crohn's disease are common human gastrointestinal diseases that share inflammation as a key driver for their development. A general outcome resulting from these chronic inflammatory conditions is increased oxidative stress. Oxidative stress is caused by the generation of reactive oxygen and nitrogen species that are part of the normal inflammatory response, but are also capable of damaging cellular DNA, protein, and organelles. Damage to DNA can include DNA strand breaks, point mutations due to DNA adducts, as well as alterations in methylation patterns leading to activation of oncogenes or inactivation of tumor suppressors. There are a number of significant long-term consequences associated with chronic oxidative stress, most notably cancer. Infiltrating immune cells and stromal components of tissue including fibroblasts contribute to dynamic changes occurring in tissue related to disease development. Immune cells can potentiate oxidative stress, and fibroblasts have the capacity to contribute to advanced growth and proliferation of the epithelium and any resultant cancers. Disease models for GERD, BE, GVHD, and ulcerative colitis based on three-dimensional human cell and tissue culture systems that recapitulate in vivo growth and differentiation in inflammatory-associated microphysiological environments would enhance our understanding of disease progression and improve our ability to test for disease-prevention strategies. The development of physiologically relevant, human cell-based culture systems is therefore a major focus of our research. These novel models will be of enormous value, allowing us to test hypotheses and advance our understanding of these disorders, and will have a translational impact allowing us to more rapidly develop therapeutic and chemopreventive agents. In summary, this work to develop advanced human cell-based models of inflammatory conditions will greatly improve our ability to study, prevent, and treat GERD, BE, GVHD, and inflammatory bowel disease. The work will also foster the development of novel therapeutic and preventive strategies that will improve patient care for these important clinical conditions

Denervation suppresses gastric tumorigenesis

The nervous system plays an important role in the regulation of epithelial homeostasis and has also been postulated to play a role in tumorigenesis. We provide evidence that proper innervation is critical at all stages of gastric tumorigenesis. In three separate mouse models of gastric cancer, surgical or pharmacological denervation of the stomach (bilateral or unilateral truncal vagotomy, or local injection of botulinum toxin type A) markedly reduced tumor incidence and progression, but only in the denervated portion of the stomach. Vagotomy or botulinum toxin type A treatment also enhanced the therapeutic effects of systemic chemotherapy and prolonged survival. Denervation-induced suppression of tumorigenesis was associated with inhibition of Wnt signaling and suppression of stem cell expansion. In gastric organoid cultures, neurons stimulated growth in a Wnt-mediated fashion through cholinergic signaling. Furthermore, pharmacological inhibition or genetic knockout of the muscarinic acetylcholine M[subscript 3] receptor suppressed gastric tumorigenesis. In gastric cancer patients, tumor stage correlated with neural density and activated Wnt signaling, whereas vagotomy reduced the risk of gastric cancer. Together, our findings suggest that vagal innervation contributes to gastric tumorigenesis via M[subscript 3] receptor–mediated Wnt signaling in the stem cells, and that denervation might represent a feasible strategy for the control of gastric cancer

NAD+ protects against EAE by regulating CD4+ T-cell differentiation

CD4+ T cells are involved in the development of autoimmunity, including multiple sclerosis (MS). Here we show that nicotinamide adenine dinucleotide (NAD+) blocks experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, by inducing immune homeostasis through CD4+IFNγ+IL-10+ T cells and reverses disease progression by restoring tissue integrity via remyelination and neuroregeneration. We show that NAD+ regulates CD4+ T-cell differentiation through tryptophan hydroxylase-1 (Tph1), independently of well-established transcription factors. In the presence of NAD+, the frequency of T-bet−/− CD4+IFNγ+ T cells was twofold higher than wild-type CD4+ T cells cultured in conventional T helper 1 polarizing conditions. Our findings unravel a new pathway orchestrating CD4+ T-cell differentiation and demonstrate that NAD+ may serve as a powerful therapeutic agent for the treatment of autoimmune and other diseases

Properties of individual contrails: a compilation of observations and some comparisons

Mean properties of individual contrails are characterized for a wide range of jet aircraft as a function of age during their life cycle from seconds to 11.5 h (7.4-18.7 km altitude, -88 to -31 degrees C ambient temperature), based on a compilation of about 230 previous in situ and remote sensing measurements. The airborne, satellite, and ground-based observations encompass exhaust contrails from jet aircraft from 1972 onwards, as well as a few older data for propeller aircraft. The contrails are characterized by mean ice particle sizes and concentrations, extinction, ice water content, optical depth, geometrical depth, and contrail width. Integral contrail properties include the cross-section area and total number of ice particles, total ice water content, and total extinction (area integral of extinction) per contrail length. When known, the contrail-causing aircraft and ambient conditions are characterized. The individual datasets are briefly described, including a few new analyses performed for this study, and compiled together to form a "contrail library" (COLI). The data are compared with results of the Contrail Cirrus Prediction (CoCiP) model. The observations confirm that the number of ice particles in contrails is controlled by the engine exhaust and the formation process in the jet phase, with some particle losses in the wake vortex phase, followed later by weak decreases with time. Contrail cross sections grow more quickly than expected from exhaust dilution. The cross-section-integrated extinction follows an algebraic approximation. The ratio of volume to effective mean radius decreases with time. The ice water content increases with increasing temperature, similar to non-contrail cirrus, while the equivalent relative humidity over ice saturation of the contrail ice mass increases at lower temperatures in the data. Several contrails were observed in warm air above the Schmidt-Appleman threshold temperature. The "emission index" of ice particles, i.e., the number of ice particles formed in the young contrail per burnt fuel mass, is estimated from the measured concentrations for estimated dilution;maximum values exceed 10(15) kg(-1). The dependence of the data on the observation methods is discussed. We find no obvious indication for significant contributions from spurious particles resulting from shattering of ice crystals on the microphysical probes

Origins of the Tumor Microenvironment: Quantitative Assessment of Adipose-Derived and Bone Marrow–Derived Stroma

To meet the requirements for rapid tumor growth, a complex array of non-neoplastic cells are recruited to the tumor microenvironment. These cells facilitate tumor development by providing matrices, cytokines, growth factors, as well as vascular networks for nutrient and waste exchange, however their precise origins remain unclear. Through multicolored tissue transplant procedures; we have quantitatively determined the contribution of bone marrow-derived and adipose-derived cells to stromal populations within syngeneic ovarian and breast murine tumors. Our results indicate that subpopulations of tumor-associated fibroblasts (TAFs) are recruited from two distinct sources. The majority of fibroblast specific protein (FSP) positive and fibroblast activation protein (FAP) positive TAFs originate from mesenchymal stem/stromal cells (MSC) located in bone marrow sources, whereas most vascular and fibrovascular stroma (pericytes, α-SMA+ myofibroblasts, and endothelial cells) originates from neighboring adipose tissue. These results highlight the capacity for tumors to utilize multiple sources of structural cells in a systematic and discriminative manner

Genome-wide association study identifies susceptibility loci for acute myeloid leukemia

Acute myeloid leukemia (AML) is a hematological malignancy with an undefined heritable risk. Here we perform a meta-analysis of three genome-wide association studies, with replication in a fourth study, incorporating a total of 4018 AML cases and 10488 controls. We identify a genome-wide significant risk locus for AML at 11q13.2 (rs4930561; P = 2.15 × 10-8; KMT5B). We also identify a genome-wide significant risk locus for the cytogenetically normal AML sub-group (N = 1287) at 6p21.32 (rs3916765; P = 1.51 × 10-10; HLA). Our results inform on AML etiology and identify putative functional genes operating in histone methylation (KMT5B) and immune function (HLA)