The Influence of Organization and Management on the Safety of NPPS and Other Complex Industrial Systems (Report of an IAEA/IIASA consultants meeting in Laxenburg and Vienna, 18-22 March 1991)

An analysis of causes for human errors reveals that deficiencies in organization and management often provide an environment making errors more likely. There is also a considerable difference between the operational performance of similar industrial plants. A closer analysis often reveals that the differences can be attributed to the managing practices. Accepting organization and management as one important precursor for operational safety, the aim is to identify good managerial structures and practices as well as characteristics of unsafe operational practices. Such information can provide guidance for the operators of the installations and also support regulatory agencies. The ultimate aim should be to detect and correct organizational deficiencies before an incident or accident brings them into the open. It is therefore not sufficient to blame individuals nor training, because management and organization establishes priorities, structures, and practices that enable tasks to be accomplished. A consultants' meeting organized jointly by the International Atomic Energy Agency (IAEA) and the International Institute for Applied Systems Analysis (IIASA) was held in Laxenburg and Vienna, Austria on 18-22 March 1991. The objective of the meeting was to assess the extent to which research within the management sciences -can provide guidance for the practical problems of managing organizations, where safety is the major concern. The influence of organization and management on the safety of complex industrial installations was discussed during the meeting and the exchange of ideas and experience between different industrial sectors and the academia proved fruitful. In spite of the difference among national and company practices it is still expected that there are many possibilities for an exchange of good managerial knowledge, experience, and practices. The report collects both the contributions offered by members of the Expert Task Force and the findings of the discussions that took place during the meeting. Specific reference is in the following text made to the nuclear industry with the understanding that the issues have a wider application to chemical plants, off-shore installations or more generally to industries where safety is a major concern

ERK1/2 is an endogenous negative regulator of the gamma-secretase activity

As an essential protease in the generation of amyloid beta, gamma-secretase is believed to play an important role in the pathogenesis of Alzheimer's disease. Although a great deal of progress has been made in identifying the components of gamma-secretase complex, the endogenous regulatory mechanism of gamma-secretase is unknown. Here we show that gamma-secretase is endogenously regulated via extracellular signal regulated MAP kinase (ERK) 1/2-dependent mitogen-activated protein kinase (MAPK) pathway. The inhibition of ERK1/2 activity, either by a treatment with a MEK inhibitor or an ERK knockdown transfection, dramatically increased gamma-secretase activity in several different cell types. JNK or p38 kinase inhibitors had little effect, indicating that the effect is specific to ERK1/2-dependent MAPK pathway. Conversely, increased ERK1/2 activity, by adding purified active ERK1/2 or EGF-induced activation of ERK1/2, significantly reduced gamma-secretase activity, demonstrating down-regulation of gamma-secretase activity by ERK1/2. Whereas gamma-secretase expression was not affected by ERK1/2, its activity was enhanced by phosphatase treatment, indicating that ERK1/2 regulates gamma-secretase activity by altering the pattern of phophorylation. Among the components of isolated gamma-secretase complex, only nicastrin was phosphorylated by ERK1/2, and it precipitated with ERK1/2 in a co-immunoprecipitation assay, which suggests binding between ERK1/2 and nicastrin. Our results show that ERK1/2 is an endogenous regulator of gamma-secretase, which raises the possibility that ERK1/2 down-regulates gamma-secretase activity by directly phosphorylating nicastrin