A Vocabulary for Visions in Designing for Transitions

Las “visiones de futuros sostenibles” se han propuesto como un componente clave del diseño para la transición, “un medio a través del cual los estilos de vida contemporáneos y las intervenciones de diseño pueden evaluarse y criticarse contra la visualización de un futuro deseado” (Irwin et al, 2015a, p. 8). Tales ambiciones son necesariamente de amplio alcance, y requieren unir líneas sobre el diseño y la especulación de diversas fuentes. Aquí buscamos aumentar el impulso explorando un conjunto de conceptos que se relacionan particularmente con este papel de visión en el diseño de transiciones. Sobre la base de perspectivas y proyectos de otros campos, presentamos elementos de un vocabulario visionario, que abarca diferentes escalas y grados de eliminación del presente, y la ubicación de estos términos en relación con los desafíos específicos y las oportunidades para el pensamiento y la práctica de la transición.“Visions of sustainable futures” have been proposed as a key component of Transition Design, “a means through which contemporary lifestyles and design interventions can be assessed and critiqued against a desired future state” (Irwin et al, 2015a, p. 8). Such ambitions are necessarily wide-ranging, and call for drawing together strands on design and speculation from diverse sources. Here we seek to add to the momentum by exploring a set of concepts relating particularly to this role of vision in designing for transitions. Building on perspectives and projects from other fields, we present elements of a visionary vocabulary, covering different scales and degrees of remove from the present, and situating these terms in relation to specific challenges and opportunities for transition thinking and practice.as visões de futuros sustentáveis se propuseram como componente chave do design para a transição, um meio através do qual os estilos de vida contemporâneos e as intervenções do design podem ser avaliadas e criticadas contra a visualização de um futuro desejado (Irwin et al, 2015a). Essas ambições são necessariamente de amplo alcance, e requerem unir linhas sobre o design e a especulação de diversas fontes. Aqui procuramos aumentar o impulso explorando um conjunto de conceitos que se relacionam particularmente com o papel de visão no design de transições. A partir de perspectivas e projetos de outros campos, apresentamos elementos de um vocabulário visionário, que abarca diferentes escalas e graus de eliminação do presente, e a localização destes términos em relação com os desafios específicos e as oportunidades para o pensamento e a prática da transição.&nbsp

Influence of the TARP γ8-selective negative allosteric modulator JNJ-55511118 on AMPA receptor gating and channel conductance

AMPARs mediate excitatory signaling in the brain and are therapeutic targets for the treatment of diverse neurological disorders. The receptors interact with a variety of auxiliary subunits, including the transmembrane AMPAR regulatory proteins (TARPs). The TARPs influence AMPAR biosynthesis and trafficking and enhance receptor responses by slowing desensitization and deactivation and increasing single-channel conductance. TARP γ8 has an expression pattern that is distinct from other TARPs, being enriched in the hippocampus. Recently, several compounds have been identified that selectivity inhibit γ8-containing AMPARs. One such inhibitor, JNJ-55511118, has shown considerable promise for the treatment of epilepsy. However, key details of its mechanism of action are still lacking. Here, using patch-clamp electrophysiological recording from heterologously expressed AMPARs, we show that JNJ-55511118 inhibits peak currents of γ8-containing AMPARs by decreasing their single-channel conductance. The drug also modifies hallmark features of AMPAR pharmacology, including the TARP-dependent actions of intracellular polyamines and the partial agonist kainate. Moreover, we find that JNJ-5551118 reduces the influence of γ8 on all biophysical measures, aside from its effect on the recovery from desensitization. The drug is also effective when applied intracellularly, suggesting it may access its binding site from within the membrane. Additionally, we find that AMPARs incorporating TARP γ2 mutated to contain the JNJ-55511118 binding site, exhibit greater block than seen with AMPARs containing γ8, potentially reflecting differences in TARP stoichiometry. Taken together, our data provide new insight into the mechanism by which γ8-selective drugs inhibit AMPARs

Molecular mechanisms contributing to TARP regulation of channel conductance and polyamine block of calcium-permeable AMPA receptors.

Many properties of fast synaptic transmission in the brain are influenced by transmembrane AMPAR regulatory proteins (TARPs) that modulate the pharmacology and gating of AMPA-type glutamate receptors (AMPARs). Although much is known about TARP influence on AMPAR pharmacology and kinetics through their modulation of the extracellular ligand-binding domain (LBD), less is known about their regulation of the ion channel region. TARP-induced modifications in AMPAR channel behavior include increased single-channel conductance and weakened block of calcium-permeable AMPARs (CP-AMPARs) by endogenous intracellular polyamines. To investigate how TARPs modify ion flux and channel block, we examined the action of γ-2 (stargazin) on GluA1 and GluA4 CP-AMPARs. First, we compared the permeation of organic cations of different sizes. We found that γ-2 increased the permeability of several cations but not the estimated AMPAR pore size, suggesting that TARP-induced relief of polyamine block does not reflect altered pore diameter. Second, to determine whether residues in the TARP intracellular C-tail regulate polyamine block and channel conductance, we examined various γ-2 C-tail mutants. We identified the membrane proximal region of the C terminus as crucial for full TARP-attenuation of polyamine block, whereas complete deletion of the C-tail markedly enhanced the TARP-induced increase in channel conductance; thus, the TARP C-tail influences ion permeation. Third, we identified a site in the pore-lining region of the AMPAR, close to its Q/R site, that is crucial in determining the TARP-induced changes in single-channel conductance. This conserved residue represents a site of TARP action, independent of the AMPAR LBD

Enhanced functional detection of synaptic calcium-permeable AMPA receptors using intracellular NASPM

Calcium-permeable AMPA-type glutamate receptors (CP-AMPARs) contribute to many forms of synaptic plasticity and pathology. They can be distinguished from GluA2-containing calcium-impermeable AMPARs by the inward rectification of their currents, which reflects voltage-dependent channel block by intracellular spermine. However, the efficacy of this weakly permeant blocker is differentially altered by the presence of AMPAR auxiliary subunits - including transmembrane AMPAR regulatory proteins, cornichons and GSG1L - which are widely expressed in neurons and glia. This complicates the interpretation of rectification as a measure of CP-AMPAR expression. Here we show that inclusion of the spider toxin analogue 1‑naphthylacetyl spermine (NASPM) in the intracellular solution results in complete block of GluA1-mediated outward currents irrespective of the type of associated auxiliary subunit. In neurons from GluA2-knockout mice expressing only CP-AMPARs, intracellular NASPM, unlike spermine, completely blocks outward synaptic currents. Thus, our results identify a functional measure of CP-AMPARs, that is unaffected by their auxiliary subunit content

GABA Transporter Deficiency Causes Tremor, Ataxia, Nervousness, and Increased GABA-Induced Tonic Conductance in Cerebellum

GABA transporter subtype 1 (GAT1) knock-out (KO) mice display normal reproduction and life span but have reduced body weight (female, -10%; male, -20%) and higher body temperature fluctuations in the 0.2-1.5/h frequency range. Mouse GAT1 (mGAT1) KO mice exhibit motor disorders, including gait abnormality, constant 25-32 Hz tremor, which is aggravated by flunitrazepam, reduced rotarod performance, and reduced locomotor activity in the home cage. Open-field tests show delayed exploratory activity, reduced rearing, and reduced visits to the central area, with no change in the total distance traveled. The mGAT1 KO mice display no difference in acoustic startle response but exhibit a deficiency in prepulse inhibition. These open-field and prepulse inhibition results suggest that the mGAT1 KO mice display mild anxiety or nervousness. The compromised GABA uptake in mGAT1 KO mice results in an increased GABA_A receptor-mediated tonic conductance in both cerebellar granule and Purkinje cells. The reduced rate of GABA clearance from the synaptic cleft is probably responsible for the slower decay of spontaneous IPSCs in cerebellar granule cells. There is little or no compensatory change in other proteins or structures related to GABA transmission in the mGAT1 KO mice, including GAT1-independent GABA uptake, number of GABAergic interneurons, and GABA_A-, vesicular GABA transporter-, GAD65-, and GAT3-immunoreactive structures in cerebellum or hippocampus. Therefore, the excessive extracellular GABA present in mGAT1 KO mice results in behaviors that partially phenocopy the clinical side effects of tiagabine, suggesting that these side effects are inherent to a therapeutic strategy that targets the widely expressed GAT1 transporter system

Expanding modes of reflection in design futuring

Design futuring approaches, such as speculative design, design fiction and others, seek to (re)envision futures and explore alternatives. As design futuring becomes established in HCI design research, there is an opportunity to expand and develop these approaches. To that end, by reflecting on our own research and examining related work, we contribute five modes of reflection. These modes concern formgiving, temporality, researcher positionality, real-world engagement, and knowledge production. We illustrate the value of each mode through careful analysis of selected design exemplars and provide questions to interrogate the practice of design futuring. Each reflective mode offers productive resources for design practitioners and researchers to articulate their work, generate new directions for their work, and analyze their own and others’ work.

The environmental setting of Epipalaeolithic aggregation site Kharaneh IV

The archaeological site of Kharaneh IV in Jordan's Azraq Basin, and its relatively near neighbour Jilat 6 show evidence of sustained occupation of substantial size through the Early to Middle Epipalaeolithic (c. 24,000 - 15,000 cal BP). Here we review the geomorphological evidence for the environmental setting in which Kharaneh IV was established. The on-site stratigraphy is clearly differentiated from surrounding sediments, marked visually as well as by higher magnetic susceptibility values. Dating and analysis of off-site sediments show that a significant wetland existed at the site prior to and during early site occupation (~ 23,000 - 19,000 BP). This may explain why such a substantial site existed at this location. This wetland dating to the Last Glacial Maximum also provides important information on the palaeoenvironments and potential palaeoclimatic scenarios for today's eastern Jordanian desert, from where such evidence is scarce