Publications

The serine-rich repeat (SRR) glycoproteins are a family of adhesins found in many Gram-positive bacteria. Expression of the SRR adhesins has been linked to virulence for a variety of infections, including streptococcal endocarditis. The SRR preproteins undergo intracellular glycosylation, followed by export via the accessory Sec (aSec) system. This specialized transporter is comprised of SecA2, SecY2 and three to five accessory Sec proteins (Asps) that are required for export. Although the post-translational modification and transport of the SRR adhesins have been viewed as distinct processes, we found that Asp2 of Streptococcus gordonii also has an important role in modifying the SRR adhesin GspB. Biochemical analysis and mass spectrometry indicate that Asp2 is an acetyltransferase that modifies N-acetylglucosamine (GlcNAc) moieties on the SRR domains of GspB. Targeted mutations of the predicted Asp2 catalytic domain had no effect on transport, but abolished acetylation. Acetylated forms of GspB were only detected when the protein was exported via the aSec system, but not when transport was abolished by secA2 deletion. In addition, GspB variants rerouted to export via the canonical Sec pathway also lacked O-acetylation, demonstrating that this modification is specific to export via the aSec system. Streptococci expressing GspB lacking O-acetylated GlcNAc were significantly reduced in their ability bind to human platelets in vitro, an interaction that has been strongly linked to virulence in the setting of endocarditis. These results demonstrate that Asp2 is a bifunctional protein involved in both the post-translational modification and transport of SRR glycoproteins. In addition, these findings indicate that these processes are coordinated during the biogenesis of SRR glycoproteins, such that the adhesin is optimally modified for binding. This requirement for the coupling of modification and export may explain the co-evolution of the SRR glycoproteins with their specialized glycan modifying and export systems.

OBJECTIVE

Lifetime stressful life events (SLEs) may predispose oncology patients to cancer-related distress (i.e., intrusive thoughts, hyperarousal, avoidance). Coping may influence cancer-related distress by mediating this relationship. This study sought to (a) determine the prevalence and impact of lifetime SLEs among oncology outpatients receiving chemotherapy and (b) examine the relationship between SLEs and cancer-related distress and the mediating role of coping on this relationship.

METHOD

Patients (n = 957), with breast, gastrointestinal, gynecologic or lung cancer, who were undergoing chemotherapy, completed the Life Stressor Checklist-Revised (LSC-R), a measure of lifetime SLEs. Cancer-related distress was assessed with the Impact of Event Scale-Revised. Coping strategies since beginning chemotherapy were assessed with the Brief COPE; 2 latent variables (engagement and disengagement coping) were identified based on these scores. LSC-R scores (number of SLEs and perceived impact during the prior year) were evaluated in relation to demographic and clinical characteristics. Structural equation modeling was used to evaluate the relationship between LSC-R and Impact of Event Scale-Revised scores and the mediating role of engagement and disengagement coping on this relationship.

RESULTS

On average, patients reported 6.1 (SD = 4.0; range = 0-23 out of 30) SLEs. Patients who were not married/partnered, had incomes <$30,000/year, or who had lower functional status or greater comorbidity had higher LSC-R scores. The relationship between more SLEs and more severe cancer-related distress was completely mediated by disengagement coping. Engagement coping did not mediate this relationship.

CONCLUSIONS

Disengagement coping, including behavioral disengagement, avoidance, and denial, should be targeted to mitigate cancer-related distress. (PsycINFO Database Record

Failure of the right ventricle (RV) is a serious disease with a poor prognosis and limited treatment options. Signaling by α-adrenergic receptors (α-ARs), in particular the α-subtype, mediate cardioprotective effects in multiple heart failure models. Recent studies have shown that chronic treatment with the α-subtype agonist A61603 improves function and survival in a model of left ventricular failure. The goal of the present study was to determine if chronic A61603 treatment is beneficial in a RV failure model. We used tracheal instillation of the fibrogenic antibiotic bleomycin in mice to induce pulmonary fibrosis, pulmonary hypertension, and RV failure within 2 wk. Some mice were chronically treated with a low dose of A61603 (10 ng·kg·day). In the bleomycin model of RV failure, chronic A61603 treatment was associated with improved RV fractional shortening and greater in vitro force development by RV muscle preparations. Cell injury markers were reduced with A61603 treatment (serum cardiac troponin I, RV fibrosis, and expression of matrix metalloproteinase-2). RV oxidative stress was reduced (using the probes dihydroethidium and 4-hydroxynonenal). Consistent with lowered RV oxidative stress, A61603 was associated with an increased level of the cellular antioxidant superoxide dismutase 1 and a lower level of the prooxidant NAD(P)H oxidase isoform NOX4. In summary, in the bleomycin model of RV failure, chronic A61603 treatment reduced RV oxidative stress, RV myocyte necrosis, and RV fibrosis and increased both RV function and in vitro force development. These findings suggest that in the context of pulmonary fibrosis, the α-subtype is a potential therapeutic target to treat the failing RV. Right ventricular (RV) failure is a serious disease with a poor prognosis and no effective treatments. In the mouse bleomycin model of RV failure, we tested the efficacy of a treatment using the α-adrenergic receptor subtype agonist A61603. Chronic A61603 treatment improved RV contraction and reduced multiple indexes of RV injury, suggesting that the α-subtype is a therapeutic target to treat RV failure.