Mast Cell Chymase and Kidney Disease

A sizable part (~2%) of the human genome encodes for proteases. They are involved in many physiological processes, such as development, reproduction and inflammation, but also play a role in pathology. Mast cells (MC) contain a variety of MC specific proteases, the expression of which may differ between various MC subtypes. Amongst these proteases, chymase represents up to 25% of the total proteins in the MC and is released from cytoplasmic granules upon activation. Once secreted, it cleaves the targets in the local tissue environment, but may also act in lymph nodes infiltrated by MC, or systemically, when reaching the circulation during an inflammatory response. MC have been recognized as important components in the development of kidney disease. Based on this observation, MC chymase has gained interest following the discovery that it contributes to the angiotensin-converting enzyme’s independent generation of angiotensin II, an important inflammatory mediator in the development of kidney disease. Hence, progress regarding its role has been made based on studies using inhibitors but also on mice deficient in MC protease 4 (mMCP-4), the functional murine counterpart of human chymase. In this review, we discuss the role and actions of chymase in kidney disease. While initially believed to contribute to pathogenesis, the accumulated data favor a more subtle view, indicating that chymase may also have beneficial actions.     

Influence of the intrinsic layer characteristics on a-Si:H p–i–n solar cell performance analysed by means of a computer simulation

In this paper a set of one-dimensional simulations of a-Si:H p–i–n junctions under different illumination conditions and with different intrinsic layer are presented. The simulation program ASCA permits the analysis of the internal electrical behaviour of the cell allowing a comparison among the different internal configurations determined by a change in the input set. Results about the internal electric configuration will be presented and discussed outlining their influence on the current tension characteristic curve. Considerations about the drift–diffusion and the generation–recombination balance distributions, outlined by the simulation, can be used to explain the correlation between the basic device output, the i-layer characteristics (thickness and DOS), the incident radiation intensity and photon energy.     

Kinetic modelling of textural changes in ready-to-eat breakfast cereals during soaking in semi-skimmed milk

Summary Ready‐to‐eat breakfast cereals immersed in milk undergo undesirable changes in texture because of sudden moisture uptake. The textural changes are ascribable to a plasticizing effect of water, which modifies the mechanical strength of products by softening the starch/protein matrix. In this work, some textural parameters of different cereal flakes were derived from the force–displacement curves monitored during 300 s of immersion in milk. Hardness loss, deformability increment and changes in the force–displacement curve profile were calculated and plotted against soaking time. The application of a sugar coating process to a model cereal flake increased the initial product hardness and improved the preservation of the textural parameters during immersion. The Peleg model closely fitted the experimental data, with regression coefficients from 0.967 to 0.999.     

Involvement of regional lymph nodes after penetration of Schistosoma mansoni cercariae in naive and infected mice

The very low density lipoprotein receptor (VLDL-r) is a cell-surface molecule specialized for the internalization of multiple diverse ligands, including apolipoprotein E (apoE)-containing lipoprotein particles, via clathrin-coated pits. Its structure is similar to the low-density lipoprotein receptor (LDL-r), although the two have substantially different systemic distributions and regulatory pathways. The present work examines the distribution of VLDL-r in the central nervous system (CNS) and in relation to senile plaques in Alzheimer disease (AD). VLDL-r is present on resting and activated microglia, particularly those associated with senile plaques (SPs). VLDL-r immunoreactivity is also found in cortical neurons. Two exons of VLDL-r mRNA are differentially spliced in the mature receptor mRNA. One set of splice forms gives rise to receptors containing (or lacking) an extracellular O-linked glycosylation domain near the transmembrane portion of the molecule. The other set of splice forms appears to be brain-specific, and is responsible for the presence or absence of one of the cysteine-rich repeat regions in the binding region of the molecule. Ratios of the receptor variants generated from these splice forms do not differ substantially across different cortical areas or in AD. We hypothesize that VLDL-r might contribute to metabolism of apoE and apoE/A beta complexes in the brain. Further characterizations of apoE receptors in Alzheimer brain may help lay the groundwork for understanding the role of apoE in the CNS and in the pathophysiology of AD.     

Effects of freezing and frozen storage on the physicochemical and sensory characteristics of four types of goat's cheese

Summary Physicochemical and organoleptic properties were studied in two batches of four different types of goat's milk cheese: fresh, washed curd, soft with surface flora, and Majorero, frozen for four months prior to ripening and/or chilled storage. Frozen storage did not produce significant changes in the rheological or sensory characteristics of the cheeses, except in the case of fresh cheese, the textural characteristics of which were adversely affected. The level of proteolysis, estimated from the amino-acid nitrogen, was higher in the pre-frozen washed curd, soft with surface flora, and Majorero cheeses. The level of lipolysis was comparable, except in the soft cheese with surface flora, which presented higher levels of free fatty acids when stored frozen before ripening.

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Einfluß des Gefrierens und der Gefrierlagerung auf die physikalisch-chemischen und organoleptischen Eigenschaften von vier Ziegenkäsen

Zusammenfassung Aus Ziegenmilch wurden jeweils zwei Chargen von vier spanischen Käsesorten hergestellt: Frischkäse, gewaschene Käsemasse, Weichkäse mit Oberflächenflora und Majorero -Käse. Von jeder Charge wurde die Hälfte gefroren gelagert und erst nach vier Monaten auf die übliche Weise gereift und/oder gekühlt aufbewahrt. Die physikalisch-chemischen und organoleptischen Eigenschaften wurden danach untersucht. Im Vergleich mit Käsen, die nicht gefroren gewesen waren, ergaben sich keine wesentlichen Unterschiede in den rheologischen und sensorischen Eigenschaften, mit Ausnahme bei den Frischkäsen, bei dem sich die Textur durch die Aufbewahrung in gefrorenem Zustand verschlechtert hatte. Der Gehalt an freien Aminosäuren, ein Maß für die Proteolyse, war höher in der gewaschenen Käsemasse, in dem Weichkäse mit Oberflächenflora und in dem Majorero-Käse, die vier Monate gefroren gewesen waren. Durch die Gefrierlagerung hatte sich der Fettabbau nicht verändert, mit Ausnahme bei dem Käse mit Oberflächenflora, bei dem der Gehalt an freien Fettsäuren erhöht war im Vergleich mit dem Käse, der nicht vier Monate gefriergelagert worden war.

     

Adenovirus-Mediated Inducible Expression of a PD-L1 Blocking Antibody in Combination with Macrophage Depletion Improves Survival in a Mouse Model of Peritoneal Carcinomatosis

Immune checkpoint inhibitors (ICIs) have demonstrated remarkable efficacy in a growing number of malignancies. However, overcoming primary or secondary resistances is difficult due to pharmacokinetics issues and side effects associated with high systemic exposure. Local or regional expression of monoclonal antibodies (mAbs) using gene therapy vectors can alleviate this problem. In this work, we describe a high-capacity adenoviral vector (HCA-EFZP-aPDL1) equipped with a mifepristone-inducible system for the controlled expression of an anti-programmed death ligand 1 (PD-L1) blocking antibody. The vector was tested in an immune-competent mouse model of colorectal cancer based on implantation of MC38 cells. A single local administration of HCA-EFZP-aPDL1 in subcutaneous lesions led to a significant reduction in tumor growth with minimal release of the antibody in the circulation. When the vector was tested in a more stringent setting (rapidly progressing peritoneal carcinomatosis), the antitumor effect was marginal even in combination with other immune-stimulatory agents such as polyinosinic-polycytidylic acid (pI:C), blocking mAbs for T cell immunoglobulin, mucin-domain containing-3 (TIM-3) or agonistic mAbs for 4-1BB (CD137). In contrast, macrophage depletion by clodronate liposomes enhanced the efficacy of HCA-EFZP-aPDL1. These results highlight the importance of addressing macrophage-associated immunoregulatory mechanisms to overcome resistance to ICIs in the context of colorectal cancer.     

Design with shape grammars and reinforcement learning

Shape grammars are a powerful and appealing formalism for automatic shape generation in computer-based design systems. This paper presents a proposal complementing the generative power of shape grammars with reinforcement learning techniques. We use simple (naive) shape grammars capable of generating a large variety of different designs. In order to generate those designs that comply with given design requirements, the grammar is subject to a process of machine learning using reinforcement learning techniques. Based on this method, we have developed a system for architectural design, aimed at generating two-dimensional layout schemes of single-family housing units. Using relatively simple grammar rules, we learn to generate schemes that satisfy a set of requirements stated in a design guideline. Obtained results are presented and discussed.