An external site controls closing of the epithelial Na+ channel ENaC.

Members of the ENaC/degenerin family of ion channels include the epithelial sodium channel (ENaC), acid-sensing ion channels (ASICs) and the nematode Caenorhabditis elegans degenerins. These channels are activated by a variety of stimuli such as ligands (ASICs) and mechanical forces (degenerins), or otherwise are constitutively active (ENaC). Despite their functional heterogeneity, these channels might share common basic mechanisms for gating. Mutations of a conserved residue in the extracellular loop, namely the 'degenerin site' activate all members of the ENaC/degenerin family. Chemical modification of a cysteine introduced in the degenerin site of rat ENaC (betaS518C) by the sulfhydryl reagents MTSET or MTSEA, results in a approximately 3-fold increase in the open probability. This effect is due to an 8-fold shortening of channel closed times and an increase in the number of long openings. In contrast to the intracellular gating domain in the N-terminus which is critical for channel opening, the intact extracellular degenerin site is necessary for normal channel closing, as illustrated by our observation that modification of betaS518C destabilises the channel closed state. The modification by the sulfhydryl reagents is state- and size-dependent consistent with a conformational change of the degenerin site during channel opening and closing. We propose that the intracellular and extracellular modulatory sites act on a common channel gate and control the activity of ENaC at the cell surface.

Audit report on the review of selected general and application controls over the State University of Iowa University of Iowa) ProTrav system for the period June 5, 2006 through July 28, 2006

Audit report on the review of selected general and application controls over the State University of Iowa University of Iowa) ProTrav system for the period June 5, 2006 through July 28, 2006

Report on a review of selected general and application controls over the Iowa Public Employees’ Retirement System (IPERS) Benefits Administration System for the period April 23, 2007 through May 16, 2007

Report on a review of selected general and application controls over the Iowa Public Employees’ Retirement System (IPERS) Benefits Administration System for the period April 23, 2007 through May 16, 2007

The TetR-type MfsR protein of the integrative and conjugative element (ICE) ICEclc controls both a putative efflux system and initiation of ICE transfer.

Integrative and conjugating elements (ICE) are self-transferable DNAs widely present in bacterial genomes, which often carry a variety of auxiliary genes of potential adaptive benefit. One of the model ICE is ICEclc, an element originally found in Pseudomonas knackmussii B13 and known for its propensity to provide its host with the capacity to metabolize chlorocatechols and 2-aminophenol. In this work, we studied the mechanism and target of regulation of MfsR, a TetR-type repressor previously found to exert global control on ICEclc horizontal transfer. By using a combination of ICEclc mutant and transcriptome analysis, gene reporter fusions, and DNA binding assays, we found that MfsR is a repressor of both its own expression and that of a gene cluster putatively coding for a major facilitator superfamily efflux system on ICEclc (named mfsABC). Phylogenetic analysis suggests that mfsR was originally located immediately adjacent to the efflux pump genes but became displaced from its original cis target DNA by a gene insertion. This resulted in divergence of the original bidirectional promoters into two separated individual regulatory units. Deletion of mfsABC did not result in a strong phenotype, and despite screening a large number of compounds and conditions, we were unable to define the precise current function or target of the putative efflux pump. Our data reconstruct how the separation of an ancestor mfsR-mfsABC system led to global control of ICEclc transfer by MfsR.

Report on the review of selected general and application controls over the State University of Iowa (University of Iowa) PeopleSoft General Ledger system for the period June 4, 2007 through July 27, 2007

Report on the review of selected general and application controls over the State University of Iowa (University of Iowa) PeopleSoft General Ledger system for the period June 4, 2007 through July 27, 2007

IκB-ζ controls the constitutive NF-κB target gene network and survival of ABC DLBCL.

Constitutive activation of the nuclear factor-κ B (NF-κB) pathway is a hallmark of the activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL). Recurrent mutations of NF-κB regulators that cause constitutive activity of this oncogenic pathway have been identified. However, it remains unclear how specific target genes are regulated. We identified the atypical nuclear IκB protein IκB-ζ to be upregulated in ABC compared with germinal center B-cell-like (GCB) DLBCL primary patient samples. Knockdown of IκB-ζ by RNA interference was toxic to ABC but not to GCB DLBCL cell lines. Gene expression profiling after IκB-ζ knockdown demonstrated a significant downregulation of a large number of known NF-κB target genes, indicating an essential role of IκB-ζ in regulating a specific set of NF-κB target genes. To further investigate how IκB-ζ mediates NF-κB activity, we performed immunoprecipitations and detected a physical interaction of IκB-ζ with both p50 and p52 NF-κB subunits, indicating that IκB-ζ interacts with components of both the canonical and the noncanonical NF-κB pathway in ABC DLBCL. Collectively, our data demonstrate that IκB-ζ is essential for nuclear NF-κB activity in ABC DLBCL, and thus might represent a promising molecular target for future therapies.

Glutamate exocytosis from astrocytes controls synaptic strength.

The release of transmitters from glia influences synaptic functions. The modalities and physiological functions of glial release are poorly understood. Here we show that glutamate exocytosis from astrocytes of the rat hippocampal dentate molecular layer enhances synaptic strength at excitatory synapses between perforant path afferents and granule cells. The effect is mediated by ifenprodil-sensitive NMDA ionotropic glutamate receptors and involves an increase of transmitter release at the synapse. Correspondingly, we identify NMDA receptor 2B subunits on the extrasynaptic portion of excitatory nerve terminals. The receptor distribution is spatially related to glutamate-containing synaptic-like microvesicles in the apposed astrocytic processes. This glial regulatory pathway is endogenously activated by neuronal activity-dependent stimulation of purinergic P2Y1 receptors on the astrocytes. Thus, we provide the first combined functional and ultrastructural evidence for a physiological control of synaptic activity via exocytosis of glutamate from astrocytes.

Convertibility, currency controls and the cost of capital in Western Europe, 1950-1999

For most of the post-war period, Europe s capital markets remained largely closed to international capital flows. Thispaper explores the costs of this policy. Using an event-study methodology, I examine the extent to which restrictions ofcurrent and capital account convertibility affected stock returns. The delayed introduction of full currency convertibilityincreased the cost of capital. Also, a string of measures designed to reduce capital mobility before the ultimate collapseof the Bretton Woods System had considerable negative effects. These findings offer an explanation for the mountingevidence suggesting that capital account liberalization facilitates growth.

Report on a review of selected general and application controls over the Iowa State University of Science and Technology payroll system for the period March 27 through May 11, 2007

Report on a review of selected general and application controls over the Iowa State University of Science and Technology payroll system for the period March 27 through May 11, 2007

Profile of male adolescents with conduct disorder on intellectual efficacy, cognitive flexibility, cognitive coping, impulsivity and alexithymia: a comparison with high-risk controls

Background and Objectives: To specify which of the documented cognitive and emotional deficits characterize adolescents with conduct disorder (CD) compared with high-risk controls. Methods: High-risk adolescent males with and without CD were compared on intellectual efficiency, cognitive flexibility, impulsivity, alexithymia, and cognitive coping strategies. Substance use was controlled for in analyses. Results: Both groups showed normal intellectual efficiency and cognitive flexibility, as weil as heightened alexithymia and bebavioral impulsivity. Youths with CD evidenced more self-defeating and black-and-white tbinking under stress, and more acting-out under negative affect, than those without CD. Conclusions: Deficits specifie to CD resided in facets of emotional functioning and cognitive coping that might be targeted by a coping skills intervention.

How competition controls team production: The case of fishing firms

Under team production, those who monitor individual productivity areusually the only ones compensated with a residual that varies withthe performance of the team. This pattern is efficient, as is shownby the prevalence of conventional firms, except for small teams andwhen specialized monitoring is ineffective. Profit sharing in repeatedteam production induces all team members to take disciplinary actionagainst underperformers through switching and separation decisions,however. Such action provides effective self-enforcemnt when themarkets for team members are competitive, even for large teams usingspecialized monitoring. The traditional share system of fishing firmsshows that for this competition to provide powerful enough incentivesthe costs of switching teams and measuring team productivity must bebellow. Risk allocation may constrain the organizational designdefined by the use of a share system. It does not account for itsexistence, however.

Report on a review of selected general and application controls over the Iowa State University of Science and Technology tuition and fees system for the period of April 11 through May 2, 2008

Report on a review of selected general and application controls over the Iowa State University of Science and Technology tuition and fees system for the period of April 11 through May 2, 2008

Report on a review of selected general and application controls over the University of Northern Iowa’s tuition and fees system for the period May 24, 2007 through July 3, 2007

Report on a review of selected general and application controls over the University of Northern Iowa’s tuition and fees system for the period May 24, 2007 through July 3, 2007

Protonation controls ASIC1a activity via coordinated movements in multiple domains.

Acid-sensing ion channels (ASICs) are neuronal Na(+)-conducting channels activated by extracellular acidification. ASICs are involved in pain sensation, expression of fear, and neurodegeneration after ischemic stroke. Functional ASICs are composed of three identical or homologous subunits, whose extracellular part has a handlike structure. Currently, it is unclear how protonation of residues in extracellular domains controls ASIC activity. Knowledge of these mechanisms would allow a rational development of drugs acting on ASICs. Protonation may induce conformational changes that control the position of the channel gate. We used voltage-clamp fluorometry with fluorophores attached to residues in different domains of ASIC1a to detect conformational changes. Comparison of the timing of fluorescence and current signals identified residues involved in movements that preceded desensitization and may therefore be associated with channel opening or early steps leading to desensitization. Other residues participated in movements intimately linked to desensitization and recovery from desensitization. Fluorescence signals of all mutants were detected at more alkaline pH than ionic currents. Their midpoint of pH dependence was close to that of steady-state desensitization, whereas the steepness of the pH fluorescence relationship was closer to that of current activation. A sequence of movements was observed upon acidification, and its backward movements during recovery from desensitization occurred in the reverse order, indicating that the individual steps are interdependent. Furthermore, the fluorescence signal of some labeled residues in the finger domain was strongly quenched by a Trp residue in the neighboring β-ball domain. Upon channel activation, their fluorescence intensity increased, indicating that the finger moved away from the β ball. This extensive analysis of activity-dependent conformational changes in ASICs sheds new light on the mechanisms by which protonation controls ASIC activity.