Characterization of a glycine receptor domain that controls the binding and gating mechanisms of the beta-amino acid agonist, taurine

The beta -amino acid, taurine, is a full agonist of the human glycine receptor al subunit when recombinantly expressed in a mammalian (HEK293) cell line, but a partial agonist of the same receptor when expressed in Xenopus oocytes. Several residues in the Ala101-Thr112 domain have previously been identified as determinants of beta -amino acid binding and gating mechanisms in Xenopus oocyte-expressed receptors. The present study used the substituted cysteine accessibility method to investigate the role of this domain in controlling taurine-specific binding and gating mechanisms of glycine receptors recombinantly expressed in mammalian cells. Asn102 and Glu103 are identified as taurine and glycine binding sites, whereas Ala101 is eliminated as a possible binding site. The N102C mutation also abolished the antagonistic actions of taurine, indicating that this site does not discriminate between the putative agonist- and antagonist-bound conformations of beta -amino acids. The effects of mutations from Lys104-Thr112 indicate that the mechanism by which this domain controls beta -amino acid-specific binding and gating processes differs substantially depending on whether the receptor is expressed in mammalian cells or Xenopus oocytes. Thr112 is the only domain element in mammalian cell-expressed GlyRs which was demonstrated to discriminate between glycine and taurine.

A single beta subunit M2 domain residue controls the picrotoxin sensitivity of alpha beta heteromeric glycine receptor chloride channels

This study investigated the residues responsible for the reduced picrotoxin sensitivity of the alpha beta heteromeric glycine receptor relative to the alpha homomeric receptor. By analogy with structurally related receptors, the beta subunit M2 domain residues P278 and F282 were considered the most likely candidates for mediating this effect. These residues align with G254 and T258 of the alpha subunit. The T258A, T258C and T258F mutations dramatically reduced the picrotoxin sensitivity of the alpha homomeric receptor. Furthermore, the converse F282T mutation in the beta subunit increased the picrotoxin sensitivity of the alpha beta heteromeric receptor. The P278G mutation in the beta subunit did not affect the picrotoxin sensitivity of the alpha beta heteromer. Thus, a ring of five threonines at the M2 domain depth corresponding to alpha subunit T258 is specifically required for picrotoxin sensitivity. Mutations to alpha subunit T258 also profoundly influenced the apparent glycine affinity. A substituted cysteine accessibility analysis revealed that the T258C sidechain increases its pore exposure in the channel open state. This provides further evidence for an allosteric mechanism of picrotoxin inhibition, but renders it unlikely that picrotoxin las an allosterically acting 'competitive' antagonist) binds to this residue.

A highly conserved c-fms gene intronic element controls macrophage-specific and regulated expression

The c fins gene encodes the receptor for macrophage colony-stimulating factor-1. This gene is expressed selectively in the macrophage cell lineage. Previous studies have implicated sequences in intron 2 that control transcript elongation in tissue-specific and regulated expression of c -fms. Four macrophage-specific deoxyribonuclease I (DNase I)-hypersensitive sites (DHSS) were identified within mouse intron 2. Sequences of these DHSS were found to be highly conserved compared with those in the human gene. A 250-bp region we refer to as the fins intronic regulatory element (FIRE), which is even more highly conserved than the c-fins proximal promoter, contains many consensus binding sites for macrophage-expressed transcription factors including Spl, PU.1, and C/EBP. FIRE was found to act as a macrophage-specific enhancer and as a promoter with an antisense orientation preference in transient transfections. In stable transfections of the macrophage line RAW264, as well as in clones selected for high and low-level c -fms mRNA expression, the presence of intron 2 increased the frequency and level of expression of reporter genes compared with those attained using the promoter alone. Removal of FIRE abolished reporter gene expression, revealing a suppressive activity in the remaining intronic sequences. Hence, FIRE is shown to be a key regulatory element in the fins gene.

Transformational leadership, corporate cultism and the spirituality paradigm: An unholy trinity in the workplace?

Leadership is a perennially popular topic in the academic and practitioner literature on management. In particular, the past twenty years have witnessed an explosive growth of interest in what has been termed 'transformational leadership' (henceforth, TL). The theory is closely linked to the growth in what has been defined as corporate culturism - an emphasis on the importance of cohereat cultures, as a means of securing competitive advantage. This article outlines the central components of TL theory, and subjects the concept to a critical analysis. In particular, similarities are identified between the components concerned and the characteristics of leadership practice in organizations generally defined as cults. This connection has been previously unremarked in the literature. These similarities are comprehensively reviewed. Trends towards what can be defined as corporate cultism in modem management practice are also discussed. We conclude that TL models are overly concerned with the achievement of corporate cohesion to the detriment of internal dissent Such dissent is a vital ingredient of effective decision-making. It is suggested that more inclusive and participatory models of the leadership process are required.

Emotion in the workplace: The new challenge for managers

Emotions in workplace settings and emotional intelligence are hot topics in management today. Leading business journals such as Fortune and Harvard Business Review have featured articles on emotional intelligence. But there is more to emotions in the workplace than just emotional intelligence. The aim of this article is to acquaint managers with intriguing new research that examines both emotional intelligence and the broader issue of emotion, which has been shown to play a powerful role in workplace settings. We show that this research has a strong potential for practical application in organizations within many broad human-resource functions such as selection, performance management, and training, as well as implications for more narrow domains like customer service. We conclude that the study of emotions in organizational settings has provided new and important insights into the way in which people in organizations behave, and we offer advice for managers to enable them to develop and to maintain a positive emotional climate in their organizations.

Parenthood and pay in Australia and the UK: evidence from workplace surveys

This article addresses the effect of parenthood on pay, examining potential reasons for-differences between Australia and the UK that are evident in spite of their similarly minimalist. male, breadwinner style approaches to work/family issues, Although cross-national differences reflect complex intersections of policy combinations, institutional frameworks, patterns of employment and gender contracts that cannot be assessed in a single analysis, the data used in this analysis uncover some of the factors that contribute to different outcomes. Motherhood penalties in the UK appear to be associated primarily with the comparatively low level of part-time earnings in that country, while higher premiums to fatherhood at least in part reflect a wider overall wage distribution. These findings reinforce the heed to interpret earnings effects of parenthood within the context of national patterns of employment and wage distribution; and highlight the breadth of strategies needed to deliver more equitable outcomes.

EMG activity of trunk muscles and torque output during isometric axial rotation exertion: a comparison between back pain patients and matched controls

Abnormal patterns of trunk muscle activity could affect the biomechanics of spinal movements and result in back pain. The present study aimed to examine electromyographic (EMG) activity of abdominal and back muscles as well as triaxial torque output during isometric axial rotation at different exertion levels in back pain patients and matched controls. Twelve back pain patients and 12 matched controls performed isometric right and left axial rotation at 100%, 70%, 50%, and 30% maximum voluntary contractions in a standing position. Surface EMG activity of rectus abdominis, external oblique, internal oblique, latissimus dorsi, iliocostalis lumborum and multifidus were recorded bilaterally. The primary torque in the transverse plane and the coupling torques in sagittal and coronal planes were measured. Results showed that there was a trend (P = 0.08) of higher flexion coupling torque during left axial rotation exertion in back pain patients. Higher activity for external oblique and lower activity for multifidus was shown during left axial rotation exertion in back pain group when compared to the control group. In right axial rotation, back pain patients exhibited lesser activity of rectus abdominis at higher levels of exertion when compared with matched controls. These findings demonstrated that decreased activation of one muscle may be compensated by overactivity in other muscles. The reduced levels of activity of the multifidus muscle during axial rotation exertion in back pain patients may indicate that spinal stability could be compromised. Future studies should consider these alternations in recruitment patterns in terms of spinal stability and internal loading. The findings also indicate the importance of training for coordination besides the strengthening of trunk muscles during rehabilitation process. (C) 2002 Orthopaedic Research Society. Published by Elsevier Science Ltd. All rights reserved.

Comparison of lumbar range of movement and lumbar lordosis in back pain patients and matched controls

Inconclusive findings have been shown in previous studies comparing lumbar range of movement (LROM) and lumbar lordosis between back pain patients and healthy subjects. In these studies, confounding variables such as age, gender, height, obesity, and pain level were usually not well controlled. The present study aimed to compare LROM and lumbar lordosis between back pain patients and matched controls. Fifteen male back pain patients and 15 age-, height-, obesity-, and physical activity-matched male controls were investigated. To minimize the effect of pain on the measurements, only patients with minimal or no pain at the time of testing were included in the study. Inclinometer technique was used for the evaluation of LROM in flexion, extension and lateral flexion as well as lumbar lordosis. A lumbar rotameter was used for measuring axial rotation. Pelvic motion was limited by a pelvic restraint device during LROM measurements. Results showed that there were no significant differences between the back pain and control groups in flexion, extension, lateral flexion and axial rotation LROM and also in lumbar lordosis. This may indicate that when a back pain patient is not in pain, LROM and lumbar lordosis may not be the measures that distinguish between back pain patients and subjects without back pain.

Social rules for managing attempted interpersonal domination in the workplace: Influence of status and gender.

The present study utilized a social rules approach to investigate the relative influence of gender and status on managers' self-evaluations of their effectiveness in handling a dominating subordinate. In the first study 84 White middle-class participants identified the prescriptive and proscriptive rules for socially appropriate responding to a stimulus situation involving a pushy subordinate. Four rule sets were identified for female and male managers and subordinates, respectively. Rule-sets shared a number of common rules and showed some variation according to gender roles. In the second study, 91 White middle-class participants rated the individual rules for importance and also rated their personal and managerial effectiveness when responding to the stimulus situation using gender- and status-consistent and gender-and status-inconsistent response strategies. Both men and women rated the female gender and status- consistent strategy as most effective, and rated the status-inconsistent strategy as less effective than a gender-inconsistent response. Results were interpreted as providing more support for a situational gender-related theory of workplace behavior, rather than a traditional gender role perspective.

Escalation of Drug Use in Early-Onset Cannabis Users vs Co-twin Controls

Context Previous studies have reported that early initiation of cannabis (marijuana) use is a significant risk factor for other drug use and drug-related problems. Objective To examine whether the association between early cannabis use and subsequent progression to use of other drugs and drug abuse/dependence persists after controlling for genetic and shared environmental influences. Design Cross-sectional survey conducted in 1996-2000 among an Australian national volunteer sample of 311 young adult (median age, 30 years) monozygotic and dizygotic same-sex twin pairs discordant for early cannabis use (before age 17 years). Main Outcome Measures Self-reported subsequent nonmedical use of prescription sedatives, hallucinogens, cocaine/other stimulants, and opioids; abuse or dependence on these drugs (including cannabis abuse/dependence); and alcohol dependence. Results Individuals who used cannabis by age 17 years had odds of other drug use, alcohol dependence, and drug abuse/dependence that were 2.1 to 5.2 times higher than those of their co-twin, who did not use cannabis before age 17 years. Controlling for known risk factors (early-onset alcohol or tobacco use, parental conflict/separation, childhood sexual abuse, conduct disorder, major depression, and social anxiety) had only negligible effects on these results. These associations did not differ significantly between monozygotic and dizygotic twins. Conclusions Associations between early cannabis use and later drug use and abuse/dependence cannot solely be explained by common predisposing genetic or shared environmental factors. The association may arise from the effects of the peer and social context within which cannabis is used and obtained. In particular, early access to and use of cannabis may reduce perceived barriers against the use of other illegal drugs and provide access to these drugs.

Abnormalities of the PTH-vitamin D axis and bone turnover markers in children, adolescents and adults with cystic fibrosis: comparison with healthy controls

Abnormalities of calcium and vitamin D metabolism in cystic fibrosis (CF) are well documented. We tested the hypothesis that alterations in calcium metabolism are related to vitamin D deficiency, and that bone resorption is increased relative to accretion in patients with CF. Calcitropic hormones, electrolytes, osteocalcin (OC) and bone alkaline phosphatase (BAP), (markers of bone mineralisation), urinary deoxypyridinoline [total (t) Dpd, a marker of bone resorption] and lumbar spine bone mineral density (LS BMD), expressed as a z-score, were measured in 149 (81 M) CF and 141 (61 M) control children aged 5.3-10.99 years, adolescents aged 11-17.99 years and adults aged 18-55.9 years. Data were analysed by multiple regression to adjust for age. In patients, FEV1% predicted and CRP (as disease severity markers), genotype and pancreatic status (PS) were recorded. The distribution of PTH differed between groups (P