Individual Actions as Community Informative Resources. A Collective Informative Systems Approach

This paper conceives communities (in this case, partnerships) as being able to become collective informative repositories of individual and collective actions that may better-inform their members. This paper presents one approach for studying if a community has become such an informative repository. The approach used here consists of introducing a formal language (Viable Systems Modelling, VSM) into one of the community nodes (a participant) and tracing if its use is seen in another node (another participant) - indicating the presence of a process of diffusion. This research design has been tested in a crime-reduction partnership in the UK. One of its members was asked to engage in the design and testing of this approach as a co-researcher. As a result, a questionnaire to map communication and control devices inside an organization was jointly developed. In keeping with VSM principles, the questionnaire encouraged participants to reflect on attenuation and amplification processes within their communications channels. To test the quality of the outcomes of this approach, members from another crime-reduction partnership were also invited to answer the survey; this was to confirm that VSM notions were not evident for those outside the development and testing of the questionnaire. The questionnaire indicated also its capability to make visible communication and organizational processes within collectives and its potential to stimulate self-organization, for those individuals who became familiar with VSM. Furthermore, this approach provided the authors with the capability to study information flows inside the two collectives, and contributed to an understanding of these flows as a model for building and maintaining a Community Informative System.     

Frequency-dependent involvement of NMDA receptors in the hippocampus: a novel synaptic mechanism

Acidic amino acids, such as l-glutamate, are believed to be excitatory neurotransmitters in the mammalian brain and exert effects on several different receptors named after the selective agonists kainate, quisqualate and N-methyl-D-aspartate (NMDA). The first two receptors collectively termed non-NMDA receptors, have been implicated in the mediation of synaptic transmission in many excitatory pathways in the central nervous system (CNS), whereas NMDA receptors, with few exceptions do not appear to be involved; this is typified in the hippocampus where there is a high density of NMDA receptors yet selective NMDA receptor antagonists, such as D-2-amino-5-phosphonovalerate (APV), do not affect synaptic potentials. NMDA receptors have, however, been shown to be involved in long-term potentiation (LTP) in the hippocampus, a form of synaptic plasticity which may be involved in learning and memory. NMDA receptors have also been found to contribute to epileptiform activity in this region. We now describe how NMDA receptors can participate during high-frequency synaptic transmission in the hippocampus, their involvement during low-frequency transmission being greatly suppressed by Mg2+. A frequency dependent alleviation of this blockade provides a novel synaptic mechanism whereby a single neurotransmitter can transmit very different information depending on the temporal nature of the input. This mechanism could account for the involvement of NMDA receptors in the initiation of LPT and their contribution, in part, to epileptic activity.     

Efficient generation and mapping of recessive developmental mutations using ENU mutagenesis

Treatment with N-ethyl-N-nitrosourea (ENU) efficiently generates single-nucleotide mutations in mice. Along with the renewed interest in this approach, much attention has been given recently to large screens with broad aims; however, more finely focused studies have proven very productive as well. Here we show how mutagenesis together with genetic mapping can facilitate the rapid characterization of recessive loci required for normal embryonic development. We screened third-generation progeny of mutagenized mice at embryonic day (E) 18.5 for abnormalities of organogenesis. We ascertained 15 monogenic mutations in the 54 families that were comprehensively analyzed. We carried out the experiment as an outcross, which facilitated the genetic mapping of the mutations by haplotype analysis. We mapped seven of the mutations and identified the affected locus in two lines. Using a hierarchical approach, it is possible to maximize the efficiency of this analysis so that it can be carried out easily with modest infrastructure and resources.     

THM1 negatively modulates mouse sonic hedgehog signal transduction and affects retrograde intraflagellar transport in cilia

Characterization of previously described intraflagellar transport (IFT) mouse mutants has led to the proposition that normal primary cilia are required for mammalian cells to respond to the sonic hedgehog (SHH) signal. Here we describe an N-ethyl-N-nitrosourea-induced mutant mouse, alien (aln), which has abnormal primary cilia and shows overactivation of the SHH pathway. The aln locus encodes a novel protein, THM1 (tetratricopeptide repeat-containing hedgehog modulator-1), which localizes to cilia. aln-mutant cilia have bulb-like structures at their tips in which IFT proteins (such as IFT88) are sequestered, characteristic of Chlamydomonas reinhardtii and Caenorhabditis elegans retrograde IFT mutants. RNA-interference knockdown of Ttc21b (which we call Thm1 and which encodes THM1) in mouse inner medullary collecting duct cells expressing an IFT88-enhanced yellow fluorescent protein fusion recapitulated the aln-mutant cilial phenotype, and live imaging of these cells revealed impaired retrograde IFT. In contrast to previously described IFT mutants, Smoothened and full-length glioblastoma (GLI) proteins localize to aln-mutant cilia. We hypothesize that the aln retrograde IFT defect causes sequestration of IFT proteins in aln-mutant cilia and leads to the overactivated SHH signaling phenotype. Specifically, the aln mutation uncouples the roles of anterograde and retrograde transport in SHH signaling, suggesting that anterograde IFT is required for GLI activation and that retrograde IFT modulates this event.     

A mutation in stratifin is responsible for the repeated epilation (Er) phenotype in mice

Stratifin (Sfn, also called 14-3-3sigma) is highly expressed in differentiating epidermis and mediates cell cycle arrest. Sfn is repressed in cancer, but its function during development is uncharacterized. We identified an insertion mutation in the gene Sfn in repeated epilation (Er) mutant mice by positional cloning. Er/+ mice expressed a truncated Sfn protein, which probably contributes to the defects in Er/Er and Er/+ epidermis and to cancer development in Er/+ mice.