<p>Physical forces play a key role in the morphogenesis of embryos. As cells and tissues change shape, grow, and migrate, they exert and respond to forces via mechanosensitive proteins and protein complexes. How the response to force is regulated is not completely understood. </p><p>Dorsal closure in Drosophila is a model system for studying cell sheet forces during morphogenesis. We demonstrate a role for mechanically gated ion channels (MGCs) in dorsal closure. Microinjection of GsMTx4 or GdCl₃, inhibitors of MGCs, blocks closure in a dose-dependent manner. UV-mediated uncaging of intracellular Ca<super>2+</super> causes cell contraction whereas the reduction of extra- and intracellular Ca<super>2+</super> slows closure. Pharmacologically blocking MGCs leads to defects in force generation via failure of actomyosin structures during closure, and impairs the ability of tissues to regulate forces in response to laser microsurgery.</p><p>We identify three genes which encode candidate MGC subunits that play a role in dorsal closure, <italic>ripped pocket</italic>, <italic>dtrpA1</italic>, and <italic>nompC</italic>. We find that knockdown of these channels either singly or in combination leads to defects in force generation and cell shapes during closure. </p><p>Our results reveal a key role for MGCs in closure, and suggest a mechanism for the coordination of force producing cell behaviors across the embryo.</p> / Dissertation

Dhahran, Saudi Arabia is home to the largest transnational oil corporation and gated suburban residential compound in the world. In exploring Saudi ARAMCO, I will undoubtedly be opening to the centerfold of all socio-cultural, religious, political, economic and pedagogical forces affecting today's geo-political affairs. The theoretical focus of my thesis comes from both a global and critical pedagogy framework that investigates the nature of asymmetrical power relations on micro, meso and macro levels. Additionally, the multiple perspectives I have gained while living in Dhahran and mediating between identities including girl, woman, South-Asian, Canadian, expatriate, student and artist have provided me with particular insights of a hermeneutical, epistemological, narrative, qualitative, phenomenological and visual nature. This has enabled me to perform rich multi-methodological research and informed written analysis. In this way, my thesis hopes to contribute to the examination of this largely un-explored phenomenon.

The Post-Fordist structure has aroused as a response to the stable/rigid configuration of Fordism that caused a bottleneck within capitalist organization since the mid 1970s. This period is also labeled as flexible accumulation that is based on the least circulation period of capital and as a result turnover time of the consumption objects. Here, consumption becomes a cultural activity besides its role of meeting material necessities and calls for a form of culture, in which the symbolic value of any object is of significance more than its use-value. Within this frame, the study selected a new form of contemporary housing provision as an exemplification area / the gated enclaves that represent a form of investment for the legitimization of values projected by the consumer culture. They are especially located at the new urban development areas, shared by high income level owners / surrounded by exclusionary devices like / walls, fences and private security mechanisms, and provide additional privatized services. This study aims at studying the modes of marketing strategies of these newly emerging housing provisions in Ankara that all are constructed around the theme of &ldquo / a distinct life style&rdquo / through their representational media. Therefore the study will investigate how the idea of distinctness is made public and by means of spatial analyses, how and to what extent the assertion of distinctness is achieved or constituted a genuine position within the academic or professional architectural culture will be investigated while such concepts as &ldquo / homogenization&rdquo / and &ldquo / distinctness&rdquo / will be also in agenda.

The glycine receptor (GlyR) mediates fast inhibitory neurotransmission in the central nervous system (CNS). Although GlyR α1 subunits are widely distributed, α3 subunits are found only on spinal cord pain sensory neurons where they mediate central inflammatory pain sensitization. Thus, the α3 subunit is a potential therapeutic target for anti-inflammatory analgesia. It is yet to be understood why α3 subunits are represented in these synapses. Thus, α3 subunit-specific modulators are required both as therapeutic leads and as pharmacological probes for basic research. The Thesis, which consists of three independent studies, investigated the molecular pharmacology of three classes of compounds at GlyRs, especially those containing the α3 subunit. The dihydropyridines (DHPs), nifedipine and nicardipine, modulate native GlyRs at micromolar concentrations. Nicardipine has a biphasic potentiating and inhibitory effect, whereas nifedipine causes inhibition only. The first study investigated the molecular mechanism by which these compounds inhibit recombinant GlyRs. The rate of onset of inhibition in the open state was accelerated by pre-application of DHP in the closed state, with the degree of acceleration proportional to the concentration of pre-applied DHP. This implies a non-inhibitory binding site close to the DHP inhibitory site. DHP inhibition was use-dependent and independent of glycine concentration, consistent with a pore-blocking mode of action. DHP sensitivity was abolished by the G2’A mutation, providing a strong case for DHP binding site in the pore. Nifedipine exhibited an approximately 10-fold higher inhibitory potency at α1-containing relative to α3-containing receptors, whereas nicardipine was only weakly selective for α1-containing GlyRs. The differential sensitivities of nifedipine and nicardipine for different GlyR isoforms suggest that DHPs may be a useful resource to screen as pharmacological tools for selectively inhibiting different synaptic GlyR isoforms. To date there are few compounds known to pharmacologically discriminate between α1 and α3 subunit-containing GlyRs. The second study stemmed from an observation that β-alanine and taurine act as weak partial agonists of α3 GlyRs but as strong partial agonists at α1 GlyRs. Using chimeras of α1 and α3 subunits, we identified the relatively structurally divergent M4 transmembrane domain and C-terminal tail as a specific determinant of the efficacy difference. As mutation of individual non-conserved M4 residues had little influence on agonist efficacies, the reduced efficacy of α3 GlyRs is most likely a distributed effect of all non-conserved M4 residues. Given the lack of contact between M4 and other transmembrane domains, the efficacy differences are probably mediated by differential interactions between the respective M4 domains and the surrounding lipid environment. The strong influence of M4 primary structure on partial agonist efficacy suggests that the relatively poorly conserved α3 GlyR M4 domain may be a promising domain to target in the search for α3 GlyR-specific modulators. β-carbolines have recently been shown to inhibit glycine receptors in a subunit-specific manner. The third study screened four structurally similar β-carbolines, harmane (HM), tryptoline (TP), norharmane (NHM) and 6-methoxyharmalan (MH) at recombinantly expressed α1, α1β, α2 and α3 glycine receptors. The four compounds exhibited only weak subunit-specificity, rendering them unsuitable as pharmacological probes. Because they displayed competitive antagonist activity, we investigated the roles of known glycine binding residues in coordinating the four compounds. The structural similarity of the compounds, coupled with the differential effects of C-loop mutations (T204A, F207Y) on compound potency, implied direct interactions between variable β-carboline groups and mutated residues. Mutant cycle analysis employing HM and NHM revealed a strong pairwise interaction between the HM methyl group and the C-loop in the region T204 and F207. These results, which define the orientation of the bound β-carbolines, were supported by molecular docking simulations. The information may also be relevant to understanding the mechanism of β-carboline binding to GABAAR where they are potent pharmacological probes. The identification of compounds that specifically abolish α3 GlyR-mediated currents should provide a useful means to investigate the physiological roles of this subunit. Drugs that potently and selectively enhance α3-subtype GlyR function may potentially serve as lead compounds since α3-subtype GlyRs have emerged as a potential therapeutic target for pain treatment. Results from studies forming the Thesis have identified several structural elements that might be useful for developing novel α3 subunit-specific drugs in the future.

Thesis (Ph. D.)--University of Washington, 2007. / Vita. Includes bibliographical references (p. 73-82).

Thesis (Ph.D.)--Indiana University, 2010. / Title from screen (viewed on April 1, 2010). Department of Pharmacology and Toxicology, Indiana University-Purdue University Indianapolis (IUPUI). Advisor(s): Theodore R. Cummins, Grant D. Nicol, Gerry S. Oxford, Andy Hudmon, John H. Schild. Includes vitae. Includes bibliographical references (leaves 232-266).

Thesis (M.Sc.). / Written for the Medical Physics Unit. Title from title page of PDF (viewed ). Includes bibliographical references.

Rett Syndrome (RTT) is a developmental disorder that affects numerous neuronal systems that underlie problems with breathing, movement, cognition and sleep. RTT is caused by mutations in the methyl-CpG-binding protein 2 (Mecp2) gene. MeCP2 is a ubiquitous protein that is found in all mature neurons and binds to methylated DNA to repress transcription; thus regulating protein expression levels in neurons. The mutations in Mecp2 affect a large number of proteins that are crucial for regulating neuronal activity. Despite the abnormal expression of many of these proteins, mice with a total loss of MeCP2 can live to adulthood and some people with RTT can live to a very late age as well. It is possible that mutations in the Mecp2 gene not only cause widespread defects, but also elicit neuroadaptive processes that may limit the impact of the MeCP2 dysfunction. To test this hypothesis we performed these studies in which we focused on how synaptic and membrane currents were altered to maintain normal neuronal activity in Mecp2-null mice. We show two examples from different neurons where neuroadaptations of ion channel expression allowed the neuron to remain viable. First, the properties of the nicotinic acetylcholine receptor (nAChR) current were altered in LC neurons in Mecp2-null mice. This was caused by changes in the nicotinic receptor subunit expression. Despite the changes in the nAChR current, the cholinergic modulation of LC neuron activity in WT and Mecp2-null mice were similar. Secondly, we show that the fast Na+ voltage-gated and the hyperpolarization-activated currents were altered in mesencephalic trigeminal V (Me5) propriosensory neurons. The changes in the hyperpolarization-activated current caused a smaller sag and post-inhibitory rebound. Opposite to what we expected, these cells were hyperexcitable. The hyperexcitability was due to changes in the fast Na+ voltage-gated current causing a decreased action potential threshold. Alterations in the ionic currents in Me5 neurons seem to be due to changes in subunit expression patterns. These results indicate that despite the complications caused by defects in the Mecp2 gene, neurons respond by rearranging receptor / ion channel expression. This reorganization allows neurons to remain viable despite the MeCP2 deficiency.

Thesis (MS en S)--Stellenbosch University, 2002. / ENGLISH ABSTRACT: Gated communities are a rapidly growing global residential occurrence and the long-term impact of this phenomenon on the urban landscape is of great importance to planners, local and provincial governments, urban decisionmakers, and legislation policies. The assignment is a comprehensive literature study, because in South Africa only the CSIR (BOUTEK) recently attempted to explain this fairly new development type. Internationally extensive studies have been conducted in the USA and Europe, although only in the last decade. In the study the term "gated community" is conceptualised, the general characteristics of gated communities, the pros and cons of the enclosed communities are discussed. The discussion focuses on the postmodern theory movement and how it relates to gated communities, with examples from the USA, especially Los Angeles. Additionally, the history of gated communities is discussed from Greek times to modern times and an overview is given of the international debate on gated communities. The debate emphasises important issues such as safety and security, exclusion, privacy, urban fragmentation and other issues. The last chapter looks at the current situation of gated communities in South Africa and the effect that apartheid had on the urban structure. Gated communities in South Africa are unique compared to other countries and a summary is given on the positive and negative features of gated communities in South Africa. The fear of crime is growing in South Africa, and the number of gated communities or enclosed neighbourhoods are growing daily, and calls for in-depth studies of this phenomenon in South Africa. Although there seems to be an increasing trend in larger cities to enclose areas, requests for neighbourhood enclosures have also been received by smaller cities and towns. Most of the metropolitan areas tend to have policies in place, or are in the process of compiling policies to regulate road closures and gated communities. / AFRIKAANSE OPSOMMING: Geslote gemeenskappe is 'n vinnig groeiende globale residensiële gebeurtenis en die langtermyn impak wat hierdie fenomeen het op stedelike landskap is baie belangrik vir beplanners, plaaslike en provinsiale regerings, stedelike besluitnemers, en wetgewende beleide. Die werkstuk is 'n omslagtige literatuurstudie, omdat in Suid-Afrika het die WNNR (BOUTEK) onlangs probeer om die taamlik nuwe ontwikkelingstipe te verklaar. Internasionale uitgebreide studies is al gedoen deur die VSA en Europa, alhoewel net in die laaste dekade. In hierdie studie word die term "geslote gemeenskappe" gekonseptualiseer, die algemene kenmerke van geslote gemeenskappe, die positiewe en negatiewe eienskappe van geslote gemeenskappe bepreek. Die bespreking fokus op die postmoderne teorie beweging en hoe dit verwant is aan geslote gemeensakppe, met voorbeelde van die VSA, veral Los Angeles. Gevolglik word daar gekyk na die geskiedenis van geslote gemeenskappe vanaf die Griekse tye tot die moderne tye en 'n oorsig word gegee van die internasionale debat op geslote gemeenskappe. Die debat beklemtoon belangrike kwessies soos veiligheid en sekuriteit, uitsluiting, privaatheid, stedelike opbreking en baie meer. Die laaste hoofstuk kyk na die huidige toestand van geslote gemeenskappe in Suid-Afrika en die effek wat apartheid gehad het op die stedelike struktuur. Geslote gemeenskappe in Suid-Afrika is uniek in vergelyking met ander lande en 'n opsomming word gegee op die positiewe en negatiewe eienskappe van geslote gemeenskappe in Suid-Afrika. Die angs vir geweld groei in Suid-Afrika en die hoeveelheid geslote gemeendskappe groei ook daagliks, en dus styg die noodsaaklikheid vir in-diepte studies van hierdie verskynsel in Suid-Afrika. Alhoewel dit wil voorkom dat daar 'n stygende tendens in groter stede is om areas te omsluit, is die aanvrae vir geslote gemeenskappe ook gekry van kleiner stede en dorpe. Meeste van die metropolitaanse areas neig om beleide in plek te hê, of is in die proses om beleide te struktureer vir die beheer van padsluitings en geslote gemeenskappe.

KCNE β-subunits modulate KCNQ1 (Q1) voltage-gate K+channels providing the current diversity required for Q1 channels to function in a wide variety of cell types and tissues. In the present thesis, the stoichiometry of KCNE1 (E1) β-subunits in functioning Q1 channels is investigated, along with the formation of heteromeric channel complexes, complexes containing 2 different KCNE β-subunits. The chemical approaches used to answer these questions were then expanded to generate a novel labeling reagent. To determine the stoichiometry of the Q1/E1 complex, I devised an iterative subunit counting approach that relies on a chemically releasable K+channel blocking reagent. The extracellularly applied reagent irreversibly blocks charybdotoxin (CTX) sensitive Q1 channels by chemically modifying E1 peptides that contain an N-terminal cysteine residue. Chemical release of the inhibitor and subsequent iterative applications of the reagent reported that Q1 channels partner with two KCNE β-subunits. To determine whether heteromeric Q1-KCNE complexes form, I synthesized a similar, but non-cleavable, K+channel blocking reagent that detects specific KCNE peptides in functioning complexes by irreversible channel inhibition. Using this “KCNE sensor”, heteromeric Q1/E1/E3, Q1/E1/E4 and Q1/E3/E4 complexes were shown to form, traffic to the cell surface and function. Using mathematical subtraction to visualize the irreversibly blocked current, the currents and gating kinetics of the different heteromeric complexes were revealed and a hierarchy of KCNE subunit modulation of Q1 channels was determined: E3>E1>>E4. Building on this technology, a chemically releasable K+ channel blocking reagent was created to specifically label KCNE β-subunits with biotin. The reagent delivers biotin to CTX sensitive Q1 channels and labeling occurs through free thiols provided by either cysteine residues or thiol modified sugars. This preliminary data demonstrates a novel strategy for labeling endogenous K+ channels in native cells.