Protein motions and dynamic effects in enzyme catalysis

The role of protein motions in promoting the chemical step of enzyme catalysed reactions remains a subject of considerable debate. Here, a unified view of the role of protein dynamics in dihydrofolate reductase catalysis is described. Recently the role of such motions has been investigated by characterising the biophysical properties of isotopically substituted enzymes through a combination of experimental and computational analyses. Together with previous work, these results suggest that dynamic coupling to the chemical coordinate is detrimental to catalysis and may have been selected against during DHFR evolution. The full catalytic power of Nature's catalysts appears to depend on finely tuning protein motions in each step of the catalytic cycle

Collective Narcissism Predicts Hypersensitivity to In-group Insult and Direct and Indirect Retaliatory Intergroup Hostility

Results of five studies (N = 1596) linked collective narcissism – a belief in in-group exaggerated greatness contingent on external validation – to direct and indirect, retaliatory hostility in response to situations collective narcissists perceived as insulting to the in-group but which fell well beyond the definition of an insult. In Turkey, collective narcissists responded with schadenfreude to the European economic crisis after feeling humiliated by the Turkish wait to be admitted to the European Union (Study 1). In Portugal, they supported hostile actions towards Germans and rejoiced in the German economic crisis after perceiving Germany’s position in the European Union as more important than the position of Portugal (Study 2). In Poland, they supported hostile actions towards the makers of a movie they found offensive to Poland (Study 3 and 5) and responded with direct and indirect hostility towards a celebrity whose jokes about the Polish government they found offensive (Study 4). Comparisons with self- and in-group positivity indices and predictors of intergroup hostility indicated that collective narcissism is the only systematic predictor of hypersensitivity to in-group insult followed by direct and indirect, retaliatory intergroup hostility

L-Carnitine Combined with Leucine Supplementation Does Not Improve the Effectiveness of Progressive Resistance Training in Healthy Aged Women

Abstract Objectives To evaluate the effect of L-carnitine (LC) in combination with leucine supplementation on muscle strength and muscle hypertrophy in aged women participating in a resistance exercise training (RET) program. Design/Setting/Participants Thirty-seven out of sixty (38.3% dropout) healthy women aged 60–75 years (mean 67.6 ± 0.7 years) completed the intervention in one of three groups. One of the supplemented groups received 1 g of L-carnitine-L-tartrate in combination with 3 g of L-leucine per day (LC+L group; n = 12), and the second supplemented group received 4 g of L-leucine per day (L group; n = 13). The control group (CON group; n = 12) received no supplementation. Intervention All three groups completed the same RET protocol involving exercise sessions twice per week for 24 weeks. Measurements Before and after the experiment, participants performed isometric and isokinetic muscle strength testing on the Biodex dynamometer. The cross-sectional areas of the major knee extensors and total thigh muscles were assessed using magnetic resonance imaging. Fasting serum levels of insulin-like growth factor-1 (IGF-1), myostatin and decorin, and plasma levels of total carnitine (TC) and trimethylamine-N-oxide (TMAO) levels were measured. Results The 24-week RET significantly increased muscle strength and muscle volume, but the group and time interactions were not significant for the muscle variables analyzed. Plasma total carnitine increased only in the LC+L group (p = 0.009). LC supplementation also caused a significant increase in plasma TMAO, which was higher after the intervention in the LC+L group than in the L (p &lt; 0.001), and CON (p = 0.005) groups. The intervention did not change plasma TMAO concentration in the L (p = 0.959) and CON (p = 0.866) groups. After the intervention serum decorin level was higher than before in both supplemented groups combined (p = 0.012), still not significantly different to post intervention CON (p = 0.231). No changes in serum IGF-1 and myostatin concentrations and no links between the changes in blood markers and muscle function or muscle volume were observed. Conclusions LC combined with leucine or leucine alone does not appear to improve the effectiveness of RET. </jats:sec

Can work ability explain the social gradient in sickness absence: a study of a general population in Sweden

<p>Abstract</p> <p>Background</p> <p>Understanding the reasons for the social gradient in sickness absence might provide an opportunity to reduce the general rates of sickness absence. The complete explanation for this social gradient still remains unclear and there is a need for studies using randomized working population samples. The main aim of the present study was to investigate if self-reported work ability could explain the association between low socioeconomic position and belonging to a sample of new cases of sick-listed employees.</p> <p>Methods</p> <p>The two study samples consisted of a randomized working population (n = 2,763) and a sample of new cases of sick-listed employees (n = 3,044), 19-64 years old. Both samples were drawn from the same randomized general population. Socioeconomic status was measured with occupational position and physical and mental work ability was measured with two items extracted from the work ability index.</p> <p>Results</p> <p>There was an association between lower socioeconomic status and belonging to the sick-listed sample among both women and men. In men the crude Odds ratios increased for each downwards step in socioeconomic status, OR 1.32 (95% CI 0.98-1.78), OR 1.53 (1.05-2.24), OR 2.80 (2.11-3.72), and OR 2.98 (2.27-3.90). Among women this gradient was not as pronounced. Physical work ability constituted the strongest explanatory factor explaining the total association between socioeconomic status and being sick-listed in women. However, among men, the association between skilled non-manual, OR 2.07 (1.54-2.78), and non-skilled manual, OR 2.03 (1.53-2.71) positions in relation to being sick-listed remained. The explanatory effect of mental work ability was small. Surprisingly, even in the sick-listed sample most respondents had high mental and physical work ability.</p> <p>Conclusions</p> <p>These results suggest that physical work ability may be an important key in explaining the social gradient in sickness absence, particularly in women. Hence, it is possible that the factors associated with the social gradient in sickness absence may differ, to some extent, between women and men.</p

Probing the Flexibility of Large Conformational Changes in Protein Structures through Local Perturbations

Protein conformational changes and dynamic behavior are fundamental for such processes as catalysis, regulation, and substrate recognition. Although protein dynamics have been successfully explored in computer simulation, there is an intermediate-scale of motions that has proven difficult to simulate—the motion of individual segments or domains that move independently of the body the protein. Here, we introduce a molecular-dynamics perturbation method, the Rotamerically Induced Perturbation (RIP), which can generate large, coherent motions of structural elements in picoseconds by applying large torsional perturbations to individual sidechains. Despite the large-scale motions, secondary structure elements remain intact without the need for applying backbone positional restraints. Owing to its computational efficiency, RIP can be applied to every residue in a protein, producing a global map of deformability. This map is remarkably sparse, with the dominant sites of deformation generally found on the protein surface. The global map can be used to identify loops and helices that are less tightly bound to the protein and thus are likely sites of dynamic modulation that may have important functional consequences. Additionally, they identify individual residues that have the potential to drive large-scale coherent conformational change. Applying RIP to two well-studied proteins, Dihdydrofolate Reductase and Triosephosphate Isomerase, which possess functionally-relevant mobile loops that fluctuate on the microsecond/millisecond timescale, the RIP deformation map identifies and recapitulates the flexibility of these elements. In contrast, the RIP deformation map of α-lytic protease, a kinetically stable protein, results in a map with no significant deformations. In the N-terminal domain of HSP90, the RIP deformation map clearly identifies the ligand-binding lid as a highly flexible region capable of large conformational changes. In the Estrogen Receptor ligand-binding domain, the RIP deformation map is quite sparse except for one large conformational change involving Helix-12, which is the structural element that allosterically links ligand binding to receptor activation. RIP analysis has the potential to discover sites of functional conformational changes and the linchpin residues critical in determining these conformational states

Organizational configuration of hospitals succeeding in attracting and retaining nurses

Organizational configuration of hospitals succeeding in attracting and retaining nurses. This paper contrasts structural and managerial characteristics of low- and high-turnover hospitals, and describes the organizational configuration of attractive hospitals. In countries facing nurse shortages and turnover, some hospitals succeed in recruiting and retaining nurses. In Magnet Hospitals, managerial practices and environmental characteristics increase nurses\u2019 job satisfaction and their commitment to the organization, which in turn decreases nurse turnover. Such an approach suggests that organizations are best understood as clusters of interconnected structures and practices, i.e. organizational configurations rather than entities whose components can be understood in isolation. From a sample of 12 hospitals whose nurse turnover was studied for 1 year, structural and organizational features of hospitals in the first and fourth quartiles, i.e. attractive (turnover11\uc68%) were contrasted. A questionnaire, including perceptions of health-related factors, job demands, stressors, work schedules, organizational climate, and work adjustments antecedent to turnover, was received from 401 nurses working in attractive hospitals (response rate - 53\uc68%) and 774 nurses in conventional hospitals (response rate \ubc 54\uc65%). Structural characteristics did not differentiate attractive and conventional hospitals, but employee perceptions towards the organization differed strikingly. Differences were observed for risk exposure, emotional demands, role ambiguity and conflicts, work-family conflicts, effort-reward imbalance and the meaning of work, all in favour of attractive hospitals (P < 0.01). Relationships with nursing management, work ability and satisfaction with working time, handover shifts and schedules were also better in attractive hospitals (P < 0.001). Job satisfaction and commitment were higher in attractive hospitals, whereas burnout and intention to leave were lower (P < 0.001). Organizational characteristics are key factors in nurse attraction and retention. Nurses face difficulties in their work situations, but some hospitals are perceived as healthy organizations. The concept of attractive institutions could serve as a catalyst for improvement in nurses\u2019 work environments in Europe

Cooperative Transition between Open and Closed Conformations in Potassium Channels

Potassium (K+) ion channels switch between open and closed conformations. The nature of this important transition was revealed by comparing the X-ray crystal structures of the MthK channel from Methanobacterium thermoautotrophicum, obtained in its open conformation, and the KcsA channel from Streptomyces lividans, obtained in its closed conformation. We analyzed the dynamic characteristics and energetics of these homotetrameric structures in order to study the role of the intersubunit cooperativity in this transition. For this, elastic models and in silico alanine-scanning mutagenesis were used, respectively. Reassuringly, the calculations manifested motion from the open (closed) towards the closed (open) conformation. The calculations also revealed a network of dynamically and energetically coupled residues. Interestingly, the network suggests coupling between the selectivity filter and the gate, which are located at the two ends of the channel pore. Coupling between these two regions was not observed in calculations that were conducted with the monomer, which emphasizes the importance of the intersubunit interactions within the tetrameric structure for the cooperative gating behavior of the channel