Loss of protein kinase C inhibition in the beta-T594M variant of the amiloride-sensitive Na+ channel

We previously reported the presence of a novel variant (beta-T594M) of the amiloride-sensitive Na+ channel (ASSC) in which the threonine residue at position 594 in the beta-subunit has been replaced by a methionine residue. Electrophysiological studies of the ASSC on Epstein-Barr virus (EBV)-transformed lymphocytes carrying this variant showed that the 8-(4-chlorophenylthio) adenosine 3':5'-cyclic monophosphate (8cpt-cAMP)-induced responses were enhanced when compared to wild-type EBV-transformed lymphocytes. Furthermore, in wild-type EBV-transformed cells, the 8cpt-cAMP-induced response was totally blocked by the phorbol ester, phorbol 12-myristate 13-acetate (PMA). This inhibitory effect of PMA was blocked by a protein kinase C inhibitor, chelerythrine. We now have identified individuals who are homozygous for this variant, and showed that PMA had no effect on the 8cpt-cAMP-induced responses in the EBV-transformed lymphocytes from such individuals. Cells heterozygous for this variant showed mixed responses to PMA, with the majority of cells partially inhibited by PMA. Our results demonstrate that an alteration in a single amino acid residue in the beta-subunit of the ASSC can lead to a total loss of inhibition to PMA, and establish the beta-subunit as having an important role in conferring a regulatory effect on the ASSC of lymphocytes.     

Ubiquitin-mediated regulation of 3-hydroxy-3-methylglutaryl-CoA reductase

Regulation of the sterol-synthesizing mevalonate pathway occurs in part through feedback-regulated endoplasmic reticulum degradation of 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-R). In yeast, the Hmg2p isozyme of HMG-R is regulated in this manner. We have tested the involvement of ubiquitination in the regulated degradation of Hmg2p, by using both genetic and direct biochemical approaches. Hmg2p degradation required the UBC7 gene, and Hmg2p protein was directly ubiquitinated. Hmg2p ubiquitination was dependent on UBC7 and was specific for the degraded yeast Hmg2p isozyme. Furthermore, Hmg2p ubiquitination was regulated by the mevalonate pathway in a manner consistent with regulation of Hmg2p stability. Thus, regulated ubiquitination appeared to be the mechanism by which Hmg2p stability is controlled in yeast. Finally, our data indicated that the feedback signal controlling Hmg2p ubiquitination and degradation was derived from farnesyl diphosphate, and thus implied conservation of an HMG-R degradation signal between yeast and mammals.     

Potentiation of lysis of leukaemia cells by a bispecific antibody to CD33 and CD16 (Fc gamma RIII) expressed by human natural killer (NK) cells

Bispecific antibodies recognizing tumour-associated antigens and trigger molecules expressed on immune effector cells have been shown to redirect cytotoxicity of several types of peripheral blood cells against relevant tumour targets. Among various effector cells, natural killer (NK) cells appear to play a role in defence against leukaemia. Here we report the successful chemical conjugation of monoclonal antibodies to CD33 and CD16 to create a bispecific antibody (BsAb 251 x 3G8). This bispecific antibody is capable of augmenting the killing of otherwise resistant leukaemia cells by peripheral blood lymphocytes (PBL), purified resting NK (R-NK) cells, and activated NK (A-NK) cells. BsAb 251 x 3G8 may play a role in the therapy of acute myeloid leukaemia (AML) through redirecting the cytotoxic activity of endogenous or adoptively transferred NK cells.     

Stimulus-elicited behavior in rapid eye movement sleep without atonia.

Alert wakefulness (W) and rapid eye movement sleep (REM) are remarkably similar on several measures of brain activity, but 2 differences in REM are reduced sensory responsiveness and atonia in postural muscles. Pontine tegmental lesions create REM without atonia (REM-A), releasing motor behavior. In 9 cats, we studied the acoustic startle reflex (ASR), orienting (OR), and ponto-geniculo-occipital waves (PGOE) elicited by tones during W, REM, REM-A, and non-REM (NREM). OR occurred in W and REM-A, being most complete in cats with the most elaborate spontaneous behavior. ASR occurred in W, NREM, and REM-A in lesioned cats. In normal cats, ASR rarely appeared in NREM and REM. PGOE had similar characteristics in both groups. The similarity of REM to W is particularly obvious when cats lack motoneuronal inhibition. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Three-dimensional stability analysis of planar straight cracks propagating quasistatically under type I loading

We calculate to first order the static stress distribution around cracks which are slightly perturbed from semi infinite straight planar geometry and are subject to type I loading. We find that both in-plane and out-of-plane perturbations give rise to local stress distributions which tend to suppress the deviations in the posterior (quasistatic) propagation of the crack.     

Interconnection of nonlinear causal systems

For nonlinear systems it is not a mathematically obvious fact that the simplest feedback system yields equations which are solvable, even when the gain in the loop is ⩽1. The authors treat this and more general issues. For example, it is not known (for a continuous-time system) if unity feedback for a plant C with gain <1 produces a well-posed system. It is shown that if the gain of C is <1 and C also loses sufficient efficiency at high frequency, then indeed the feedback system is well posed. The hypothesis that the gain of C is <1 can be replaced by the reasonable assumption that C saturates on large enough signals, and well posedness is still obtained. This approach also applies directly to electrical circuit connections. It is proved that rather general connections of amplifiers are well posed under the assumption that the amplifiers saturate and that they lose efficiency at high frequency     

The validity of an alternative five-factor measure of personality in cocaine abusers.

The validity of an alternative 5-factor measure of personality, the Zuckerman-Kuhlman Personality Questionnaire (ZKPQ), was assessed in 450 cocaine abusers seeking outpatient treatment. As predicted, the ZKPQ Impulsive Sensation Seeking (ImpSS), Neuroticism-Anxiety (N-Anx), and Aggression-Hostility (Agg-Hos) scales were associated with greater drug abuse and psychiatric severity and symptoms and worse outcome (p?     

Reliability of personality disorder symptoms and personality traits in substance-dependent inpatients.

The authors compared the internal consistency, 1-year temporal stability and self-informant agreement of ratings of personality trait (NEO Five-Factor Inventory; NEO-FFI; P. T. Costa & R. R. McCrae, 1992) and personality disorder symptom severity (Structured Clinical Interview for DSM-III-R personality Disorders Questionnaire; SCID-II-Q ; R. L. Spitzer, J. B. W. Williams, M. Gibbon, & M. First, 1990) in 131 substance-dependent inpatients. Internal consistency coefficients were acceptable to very good for most NEO-FFI and SCID-II-Q scales, and temporal stability correlations were significant for all measures. Agreement between patient and informant ratings was more modest. Substance abuse and depression symptom severity moderated the temporal stability and self-informant agreement of several personality trait and disorder ratings. The authors did not find that the five factors were more reliable than the Axis II symptoms. Issues related to the reliability of personality assessment in multiply diagnosed patients are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Double aperture double-gate vertical high-electron-mobility transistor

In this paper, we propose a double aperture double-gate AlGaN/GaN vertical high-electron-mobility transistor (HEMT) to improve the device characteristics, such as the current and the ON resistance (\(\hbox {\textit{R}}_{\mathrm{ON}}\)). The proposed vertical HEMT results are compared to the conventional single aperture single-gate vertical HEMT of equal dimensions, and increased drain current and lower \(\hbox {\textit{R}}_{\mathrm{ON}}\) are shown. A comprehensive simulation study has also been carried out for the proposed device, to analyse the impact of thickness and doping concentration of aperture, drift region, and current blocking layer. In addition, the effect of different materials in current blocking layer on device characteristics is also studied. The obtained results and their effect on device characteristics have been thoroughly analysed and explained accordingly.