DMT1 Protects Macrophages from Salmonella Infection by Controlling Cellular Iron Turnover and Lipocalin 2 Expression

Macrophages are at the center of innate pathogen control and iron recycling. Divalent metal transporter 1 (DMT1) is essential for the uptake of non-transferrin-bound iron (NTBI) into macrophages and for the transfer of transferrin-bound iron from the endosome to the cytoplasm. As the control of cellular iron trafficking is central for the control of infection with siderophilic pathogens such as Salmonella Typhimurium, a Gram-negative bacterium residing within the phagosome of macrophages, we examined the potential role of DMT1 for infection control. Bone marrow derived macrophages lacking DMT1 (DMT1fl/fl^LysMCre(+)) present with reduced NTBI uptake and reduced levels of the iron storage protein ferritin, the iron exporter ferroportin and, surprisingly, of the iron uptake protein transferrin receptor. Further, DMT1-deficient macrophages have an impaired control of Salmonella Typhimurium infection, paralleled by reduced levels of the peptide lipocalin-2 (LCN2). LCN2 exerts anti-bacterial activity upon binding of microbial siderophores but also facilitates systemic and cellular hypoferremia. Remarkably, nifedipine, a pharmacological DMT1 activator, stimulates LCN2 expression in RAW264.7 macrophages, confirming its DMT1-dependent regulation. In addition, the absence of DMT1 increases the availability of iron for Salmonella upon infection and leads to increased bacterial proliferation and persistence within macrophages. Accordingly, mice harboring a macrophage-selective DMT1 disruption demonstrate reduced survival following Salmonella infection. This study highlights the importance of DMT1 in nutritional immunity and the significance of iron delivery for the control of infection with siderophilic bacteria.     

Man or Boy? Probleme der Rekursion in Compilern

Eingegangen am 20.03.1996, in überarbeiteter Form am 17.02.1997     

Automatic Task-Based Code Generation for High Performance Domain Specific Embedded Language

Providing high level tools for parallel programming while sustaining a high level of performance has been a challenge that techniques like Domain Specific Embedded Languages try to solve. In previous works, we investigated the design of such a DSEL—NT\(^2\)—providing a Matlab -like syntax for parallel numerical computations inside a C++ library. In this paper, we show how NT\(^2\!\) has been redesigned for shared memory systems in an extensible and portable way. The new NT\(^2\!\) design relies on a tiered Parallel Skeleton system built using asynchronous task management and automatic compile-time taskification of user level code. We describe how this system can operate various shared memory runtimes and evaluate the design by using two benchmarks implementing linear algebra algorithms.     

Influence of a reduced wearing time on the attenuation of hearing protectors assessed via temporary threshold shifts

Valuable recommendations for the choice, utilization, care, and maintenance, and for the measurement of sound attenuation of hearing-protective devices have been laid down in international standards. Yet, by considering the wearing time of a hearing protector, the standard DIN EN 458 assumes a scarcely understandable drastic reduction in the effective attenuation even when the device is not used for only a short time in a noise-filled area. A 30 dB sound attenuation of such a protective device would, e.g., decrease to 12 dB if it were unused for only 30 min of an 8 h shift. Thus, the actual influence of a shortened wearing time on the protection of earmuffs was tested in a laboratory study using audiometric measurements of the temporary threshold shift (TTS₂) and its recovery after exposure to noise. For that purpose, the effectiveness of a hearing-protective device depending on the amount of time worn as prognosticated by DIN EN 458 was compared with the actual physiological effect of the earmuffs. Ten test subjects (Ss) participated in three test series (TS), each. In the first of the TS, the Ss were exposed to a sound pressure of 106 dB(A) for 1 h, during which the Ss wore noise-insulating earmuffs with an attenuation of 30 dB. The Ss were exposed to the same sound pressure in TS II; however, after 30 min, the earmuffs were removed for a duration of  min. Mathematically, this reduced the sound attenuation of the earmuffs to 12 dB, i.e., the average noise level over 1 h is 94 dB, which is equivalent to 85 dB(A) over 8 h. In order to evaluate the actual additional physiological cost of TS II, the Ss were exposed to 94 dB(A)/1 h without earmuffs in a third TS. This acoustic load, which is energy equivalent to the load in TS II, is also equivalent to 85 dB(A)/8 h. The results show that the continuous wearing of the earmuffs offers secure protection. However, the energetic approach and the levelling of differently structured noise loads according to the principle of energy equivalence leads to misconceiving results. The drastic reduction of the sound attenuation of the earmuffs predicted from the energetic point of view must be regarded as exaggerated. The TTS values show that TS II – which, according to the principle of energy-damage-equivalence, should result in the same effects as TS III – represents significantly less auditory fatigue. Thus, if the earmuffs are taken off briefly, a drastic reduction in the protection – as predicted in DIN EN 458 — does not result.

Relevance to industry

The results of this study demonstrate that the standards and regulations for noise rating do not correspond with the actual physiological facts and, therefore, can only be used in a very limited manner. Utilization of the principle of energy equivalence has proven problematic not only for rating noise. This principle also leads to an essential underestimation of the attenuation of hearing protectors when these devices are taken off for only a short time in a noise-filled area.     

Endocrine disrupting nonylphenols are ubiquitous in food

4-Nonylphenols (NPs) are common products of biodegradation of a widely used group of nonionic surfactants, the nonylphenol ethoxylates (NPEs). These compounds are known to be persistent, toxic, and estrogen active. There is a worldwide scientific and public discussion on the potential consequences of human long term dietary exposure to such endocrine disrupters. Despite numerous determinations of NPs in environmental samples no systematical reports exist relating to concentrations of NPs in food. We analyzed NPs in 60 different foodstuff commercially available in Germany. The results indicate that NPs are ubiquitous in food. The concentrations of NPs on a fresh weight basis varied between 0.1 and 19.4 microg/kg regardless of the fat content of the foodstuff. Based on data on German food consumption rates and these first analyses of NPs in food, the daily intake for an adult was calculated to be 7.5 microg/day NPs. For infants exclusively fed with breast milk or infant formulas daily intakes of 0.2 microg/day and 1.4 microg/day NPs, respectively, can be estimated.     

Open-loop and feedback-controlled mouse cursor movements in linear paths

Path length (A), path width (W) and movement direction (θ) are identified as the main factors affecting visually-controlled movement times in linear paths. Effects of A and W are well described by Drury's ( 1971 . Movements with lateral constraint. Ergonomics, l4 (2), 293-305.) model in which movement time is linearly related to the ratio of A/W. At low A/W values, departure from linearity has been identified but not investigated in detail. Data are presented for both open-loop and feedback-controlled movements in linear paths at 0, 60 and 150° movement directions. Movement amplitude and path width were varied over a wide range to determine the effects of A and (A/W) on movement time. Movements were found to be made ballistically or in open-loop mode when the ratio (A/W) was less than about 8 to 10 and the movement times were linearly related to √A for all angles of movement. Feedback-controlled movements followed Drury's law; ballistic movements had movement speed linear with √A. PRACTITIONER SUMMARY: Many tasks require manoeuvring equipment or devices through a path of limited width. These movements can be made with or without feedback control, depending on the path constraints. The conditions for the two forms of movement are determined in this research.     

利用Nelder-Mead单纯形法优化模糊逻辑控制器

本文提出了一种优化模糊逻辑控制器的新方法。该方法的主要思想是自动地优化误差变化率的隶属度函数，因为这类录属度函数表征了速度的反馈。为此，首先定义了一族参数化的隶属度函数，然后，在系统的运行过程中利用Ｎｅｌｄｅｒ－Ｍｅａｄ单纯算法来优化这类隶属度函数，为了验证所提方法的有效法，报告了控制一非线性被控对象的阶跃与跟踪响应。     

Mixing processes in liquid fluidized beds

The degree of mixing in the liquid phase of bench scale fluidized beds of 14 cm diameter was measured by means of a tracer technique and the Peclet numbers for transversal, longitudinal and back-mixing were evaluated using a two-dimensional dispersion model. They were investigated as functions of liquid flow rate, mean particle diameter and bed height for narrow and broad range of particle diameters and were interconnected by the Taylor—Aris relation.