Co-Chaperones in Targeting and Delivery of Misfolded Proteins to the 26S Proteasome

Protein homeostasis (proteostasis) is essential for the cell and is maintained by a highly conserved protein quality control (PQC) system, which triages newly synthesized, mislocalized and misfolded proteins. The ubiquitin-proteasome system (UPS), molecular chaperones, and co-chaperones are vital PQC elements that work together to facilitate degradation of misfolded and toxic protein species through the 26S proteasome. However, the underlying mechanisms are complex and remain partly unclear. Here, we provide an overview of the current knowledge on the co-chaperones that directly take part in targeting and delivery of PQC substrates for degradation. While J-domain proteins (JDPs) target substrates for the heat shock protein 70 (HSP70) chaperones, nucleotide-exchange factors (NEFs) deliver HSP70-bound substrates to the proteasome. So far, three NEFs have been established in proteasomal delivery: HSP110 and the ubiquitin-like (UBL) domain proteins BAG-1 and BAG-6, the latter acting as a chaperone itself and carrying its substrates directly to the proteasome. A better understanding of the individual delivery pathways will improve our ability to regulate the triage, and thus regulate the fate of aberrant proteins involved in cell stress and disease, examples of which are given throughout the review

Patient Electronic Health Data-Driven Approach to Clinical Decision Support

This article presents a novel visual analytics (VA)‐based clinical decision support (CDS) tool prototype that was designed as a collaborative work between Renaissance Computing Institute and Duke University. Using Major Depressive Disorder data from MindLinc electronic health record system at Duke, the CDS tool shows an approach to leverage data from comparative population (patients with similar medical profile) to enhance a clinicians’ decision making process at the point of care. The initial work is being extended in collaboration with the University of North Carolina CTSA to address the key challenges of CDS, as well as to show the use of VA to derive insight from large volumes of Electronic Health Record patient data. Clin Trans Sci 2011; Volume 4: 369–37

Sandwich Technique for Large Osteochondral Lesions of the Knee

Objective To evaluate whether a sandwich technique procedure for large osteochondral lesions (OCL) of the medial femur condyle reduces clinical symptoms and improves activity level as well as to assess repair tissue integration on MRI over 2 years. Design Twenty-one patients (median age: 29 years, 18-44 years) who received matrix-associated autologous chondrocyte transplantation (MACT) combined with cancellous bone grafting at the medial femur condyle in a 1-step procedure were prospectively included. Patients were evaluated before surgery (baseline) as well as 3, 6, 12, and 24 months postoperatively, including clinical evaluation, Lysholm score, Tegner Activity Rating Scale, and MRI with Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) score and a modified Whole-Organ Magnetic Resonance Imaging Score (WORMS). Results Seventeen patients were available for the 24-month (final) follow-up (4 dropouts). Lysholm significantly improved from 48 preoperatively stepwise to 95 at final follow-up (P < 0.05). Tegner improvement from 2.5 at baseline to 4.0 at final follow-up was not significant (P = 1.0). MOCART score improved significantly and stepwise from 65 at 3 months to 90 at 24 months (P < 0.05). Total WORMS improved from 14.5 at surgery to 7.0 after 24 months (P < 0.05). Body mass index and defect size at surgery correlated with total WORMS at final follow-up (P < 0.05) but did not correlate with clinical scores or defect filling. Conclusion MACT combined with cancellous bone grafting at the medial femoral condyle reduces symptoms continuously over 2 years. A 1-step procedure may reduce perioperative morbidity. However, despite improvements, patients' activity levels remain low, even 2 years after surgery

The effectiveness of antidepressant monotherapy in a naturalistic outpatient setting

10.4088/PCC.12m01364Primary Care Companion to the Journal of Clinical Psychiatry145