Inhibition of arylpyruvate oxidase by chelating agents

Zusammenfassung Die Hemmung der Phenylpyruvat- undp-Hydroxyphenylpyruvat-Oxydasen durch Chelat-Wirkstoffe wurde offenbar durch die Bildung eines Enzym-Wirkstoff-Komplexes verursacht, der bei Behandlung mit Kationen oder mit Sephadex trennbar ist. Die Reinigung des Enzyms führt zur Kupferanreicherung des Präparates, welches eine scheinbar funktionelle Einheit mit dem Enzym bildet.

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This work was supported in part by Research Grant No. MH-02278 from the National Institute of Mental Health, U.S.P.H.S.

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We wish to thank Dr.W. A. Bulen for helpful discussions about the mechanism of inhibition, and Dr.M. D. Armstrong for his encouragement during this project.     

Spontaneous miniature activity and gradation of transmission at the neuromuscular junction

Zusammenfassung Aus den bisher veröffentlichten experimentellen Befunden über presynaptische, für die neuromuskuläre Erregungsübertragung massgeblich erscheinende Vorgänge wird geschlossen, dass die Förderung der Erregungsübertragung in direkter Beziehung zur Grösse des Aktionspotentials in den motorischen Nervenendigungen steht, während die Frequenz der spontanen Miniaturentladungen an sich kein eindeutiges Mass für die Intensität des Übertragungsvorganges von Nervimpulsen zum Muskel darstellt.     

Suppression and enhancement of humoral immune response toToxoplasma gondii by passive antibody

Summary Anti-toxoplasma antibodies administered passively to mice may lead to suppression or enhancement (reported for the first time with Protozoan parasites) of subsequent antibody response when these animals are later infected withToxoplasma gondii. The outcome is dependent on infecting strain of Toxoplasma and the antigen-antibody ratio.     

Dihydrobenzothiadiazine dioxides with potent diuretic effect

Zusammenfassung Die Gewinnung eines neuen, tierexperimentell und klinisch hochwirksamen Diureticums der Formel III (6-Chlor-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazin-1,1-dioxyd) wird beschrieben.      

Targeted mutation of Cyln2 in the Williams syndrome critical region links CLIP-115 haploinsufficiency to neurodevelopmental abnormalities in mice

Williams syndrome is a neurodevelopmental disorder caused by the hemizygous deletion of 1.6 Mb on human chromosome 7q11.23. This region comprises the gene CYLN2, encoding CLIP-115, a microtubule-binding protein of 115 kD. Using a gene-targeting approach, we provide evidence that mice with haploinsufficiency for Cyln2 have features reminiscent of Williams syndrome, including mild growth deficiency, brain abnormalities, hippocampal dysfunction and particular deficits in motor coordination. Absence of CLIP-115 also leads to increased levels of CLIP-170 (a closely related cytoplasmic linker protein) and dynactin at the tips of growing microtubules. This protein redistribution may affect dynein motor regulation and, together with the loss of CLIP-115-specific functions, underlie neurological alterations in Williams syndrome.     

Nonlinear dynamics of ice-wedge networks and resulting sensitivity to severe cooling events

Patterns of subsurface wedges of ice that form along cooling-induced tension fractures, expressed at the ground surface by ridges or troughs spaced 10 30 m apart, are ubiquitous in polar lowlands. Fossilized ice wedges, which are widespread at lower latitudes, have been used to infer the duration and mean temperature of cold periods within Proterozoic and Quaternary climates, and recent climate trends have been inferred from fracture frequency in active ice wedges. Here we present simulations from a numerical model for the evolution of ice-wedge networks over a range of climate scenarios, based on the interactions between thermal tensile stress, fracture and ice wedges. We find that short-lived periods of severe cooling permanently alter the spacing between ice wedges as well as their fracture frequency. This affects the rate at which the widths of ice wedges increase as well as the network's response to subsequent climate change. We conclude that wedge spacing and width in ice-wedge networks mainly reflect infrequent episodes of rapidly falling ground temperatures rather than mean conditions.     

TLR signalling augments macrophage bactericidal activity through mitochondrial ROS

Reactive oxygen species (ROS) are essential components of the innate immune response against intracellular bacteria and it is thought that professional phagocytes generate ROS primarily via the phagosomal NADPH oxidase machinery. However, recent studies have suggested that mitochondrial ROS (mROS) also contribute to mouse macrophage bactericidal activity, although the mechanisms linking innate immune signalling to mitochondria for mROS generation remain unclear. Here we demonstrate that engagement of a subset of Toll-like receptors (TLR1, TLR2 and TLR4) results in the recruitment of mitochondria to macrophage phagosomes and augments mROS production. This response involves translocation of a TLR signalling adaptor, tumour necrosis factor receptor-associated factor 6 (TRAF6), to mitochondria, where it engages the protein ECSIT (evolutionarily conserved signalling intermediate in Toll pathways), which is implicated in mitochondrial respiratory chain assembly. Interaction with TRAF6 leads to ECSIT ubiquitination and enrichment at the mitochondrial periphery, resulting in increased mitochondrial and cellular ROS generation. ECSIT- and TRAF6-depleted macrophages have decreased levels of TLR-induced ROS and are significantly impaired in their ability to kill intracellular bacteria. Additionally, reducing macrophage mROS levels by expressing catalase in mitochondria results in defective bacterial killing, confirming the role of mROS in bactericidal activity. These results reveal a novel pathway linking innate immune signalling to mitochondria, implicate mROS as an important component of antibacterial responses and further establish mitochondria as hubs for innate immune signalling.     

Biological weapons

Adequate public health preparedness for bioterrorism includes the elaboration of an agreed list of biological and chemical agents that might be used in an attack or as threats of deliberate release. In the absence of counterterrorism intelligence information, public health authorities can also base their preparedness on the agents for which the national health structures would be most vulnerable. This article aims to describe a logical method and the characteristics of the variables to be brought in a weighing process to reach a priority list for preparedness. The European Union, in the aftermath of the anthrax events of October 2001 in the United States, set up a task force of experts from multiple member states to elaborate and implement a health security programme. One of the first tasks of this task force was to come up with a list of priority threats. The model, presented here, allows Web-based updates for newly identified agents and for the changes occurring in preventive measures for agents already listed. The same model also allows the identification of priority protection action areas.