From the Cover: Staphylococcus aureus secretes a unique class of neutrophil serine protease inhibitors

Neutrophils are indispensable for clearing infections with the prominent human pathogen Staphylococcus aureus. Here, we report that S. aureus secretes a family of proteins that potently inhibits the activity of neutrophil serine proteases (NSPs): neutrophil elastase (NE), proteinase 3, and cathepsin G. The NSPs, but not related serine proteases, are specifically blocked by the extracellular adherence protein (Eap) and the functionally orphan Eap homologs EapH1 and EapH2, with inhibitory-constant values in the low-nanomolar range. Eap proteins are together essential for NSP inhibition by S. aureus in vitro and promote staphylococcal infection in vivo. The crystal structure of the EapH1/NE complex showed that Eap molecules constitute a unique class of noncovalent protease inhibitors that occlude the catalytic cleft of NSPs. These findings increase our insights into the complex pathogenesis of S. aureus infections and create opportunities to design novel treatment strategies for inflammatory conditions related to excessive NSP activity.Infections with the human pathogen Staphylococcus aureus constitute a major risk to human health. Although this bacterium harmlessly colonizes more than 30% of the population via the nose or skin, it causes severe morbidity and mortality upon invasion of deeper tissues (1). To avert these serious infections, neutrophils play an indispensable role (2). Neutrophil serine proteases (NSPs), including neutrophil elastase (NE), proteinase 3 (PR3), and cathepsin G (CG), are important for various neutrophil functions. Active NSPs are stored within the azurophilic granules (3), but upon neutrophil activation, they either enter the nucleus to regulate extracellular trap (NET) formation (4) or they are released into the extracellular milieu to kill certain bacteria (5), cleave bacterial virulence factors (5, 6), or regulate immune responses by cleaving chemokines and receptors (7). Recently, a fourth neutrophil serine protease, denoted NSP4, was identified (8).Given the central role of NSPs in neutrophil function, we wondered whether S. aureus had evolved mechanisms to cope with NSPs. In this study, we discover that S. aureus secretes a family of proteins that specifically and potently block NSPs: extracellular adherence protein (Eap) and the hitherto functional orphans Eap-homologue (EapH) 1 and 2. Structural studies presented here show that Eap molecules represent a unique class of noncovalent NSP inhibitors that is distinct from the well-known chelonianin class of inhibitors. These mechanistic insights can initiate development of novel, broad-range NSP inhibitors to be used in various inflammatory conditions. Furthermore, these insights increase our understanding of the pathogenicity of S. aureus and underline the exceptional capability of this pathogen to adapt to its host by modulating the immune response.     

Emotional Exhaustion and Cognitive Performance in Apparently Healthy Teachers: A Longitudinal Multi‐source Study

We investigate how emotional exhaustion (EE), the core component of burnout, relates to cognitive performance, job performance and health. Cognitive performance was assessed by self‐rated cognitive stress symptoms, self‐rated and peer‐rated cognitive impairments in everyday tasks and a neuropsychological test of learning and memory (LGT‐3); job performance and physical health were gauged by self‐reports. Cross‐sectional linear regression analyses in a sample of 100 teachers confirm that EE is negatively related to cognitive performance as assessed by self‐rating and peer‐rating as well as neuropsychological testing (all p < .05). Longitudinal linear regression analyses confirm similar trends (p < .10) for self‐rated and peer‐rated cognitive performance. Executive control deficits might explain impaired cognitive performance in EE. In longitudinal analyses, EE also significantly predicts physical health. Contrary to our expectations, EE does not affect job performance. When reversed causation is tested, none of the outcome variables at Time 1 predict EE at Time 2. This speaks against cognitive dysfunctioning serving as a vulnerability factor for exhaustion. In sum, results underpin the negative consequences of EE for cognitive performance and health, which are relevant for individuals and organizations alike. In this way, findings might contribute to the understanding of the burnout syndrome. Copyright © 2012 John Wiley & Sons, Ltd.     

Adaptive screening for depression — Recalibration of an item bank for the assessment of depression in persons with mental and somatic diseases and evaluation in a simulated computer-adaptive test environment

Objective

This study conducted a simulation study for computer-adaptive testing based on the Aachen Depression Item Bank (ADIB), which was developed for the assessment of depression in persons with somatic diseases. Prior to computer-adaptive test simulation, the ADIB was newly calibrated.

Methods

Recalibration was performed in a sample of 161 patients treated for a depressive syndrome, 103 patients from cardiology, and 103 patients from otorhinolaryngology (mean age 44.1, SD = 14.0; 44.7% female) and was cross-validated in a sample of 117 patients undergoing rehabilitation for cardiac diseases (mean age 58.4, SD = 10.5; 24.8% women). Unidimensionality of the itembank was checked and a Rasch analysis was performed that evaluated local dependency (LD), differential item functioning (DIF), item fit and reliability. CAT-simulation was conducted with the total sample and additional simulated data.

Results

Recalibration resulted in a strictly unidimensional item bank with 36 items, showing good Rasch model fit (item fit residuals < |2.5|) and no DIF or LD. CAT simulation revealed that 13 items on average were necessary to estimate depression in the range of − 2 and + 2 logits when terminating at SE ≤ 0.32 and 4 items if using SE ≤ 0.50. Receiver Operating Characteristics analysis showed that θ estimates based on the CAT algorithm have good criterion validity with regard to depression diagnoses (Area Under the Curve ≥ .78 for all cut-off criteria).

Conclusion

The recalibration of the ADIB succeeded and the simulation studies conducted suggest that it has good screening performance in the samples investigated and that it may reasonably add to the improvement of depression assessment.