Establishing the entatic state in folding metallated Pseudomonas aeruginosa azurin

Understanding how the folding of proteins establishes their functional characteristics at the molecular level challenges both theorists and experimentalists. The simplest test beds for confronting this issue are provided by electron transfer proteins. The environment provided by the folded protein to the cofactor tunes the metal's electron transport capabilities as envisioned in the entatic hypothesis. To see how the entatic state is achieved one must study how the folding landscape affects and in turn is affected by the metal. Here, we develop a coarse-grained functional to explicitly model how the coordination of the metal (which results in a so-called entatic or rack-induced state) modifies the folding of the metallated Pseudomonas aeruginosa azurin. Our free-energy functional-based approach directly yields the proper nonlinear extra-thermodynamic free energy relationships for the kinetics of folding the wild type and several point-mutated variants of the metallated protein. The results agree quite well with corresponding laboratory experiments. Moreover, our modified free-energy functional provides a sufficient level of detail to explicitly model how the geometric entatic state of the metal modifies the dynamic folding nucleus of azurin

Blood Pressure and Age Are the Main Determinants of Aortic Stiffness

WOS: 000418303200017PubMed ID: 28982100

The role of the Candida biofilm matrix in drug and immune protection

This is the final version. Available on open access from Elsevier via the DOI in this recordWellcome TrustMedical Research Council (MRC)National Institute for Health and Care Research (NIHR

Impact of Using Different Stocking Rates of Goats Under Pine Plantation on Plant Species Occurrence and Animal Productivity

Abstract The study assessed the impact of using different stocking rates of goats under pine plantation on plant species occurrence and animal productivity. It was conducted on an 11 year-old loblolly pine plantation site in Epes, Alabama from July to October 2011. Thirty-six Kiko crossbred male goat kids of 4 to 5 months of age were assigned to different stocking rates, namely, low (4 goats/acre), medium (8 goats/acre), and high (12 goats/acre) with three replications each. Forage composition, animal daily gain (ADG) and blood urea nitrogen (BUN) were monitored. Bahia grass (Paspalum notatum) was the most dominant grass species across all treatments. Quantities of understory plant species decreased across all stocking densities with season, but there were no statistical differences (p \u3e 0.05); ADG and BUN were similar. Long-term studies need to be conducted before any meaningful inferences can be drawn. Keywords: Silvopasture, Loblolly Pine, Goats, Understory Species Compositio

The role of lymphoid tissue SPARC in the pathogenesis and response to treatment of multiple myeloma.

BACKGROUND: Despite the significant progress in the treatment of multiple myeloma (MM), the disease remains untreatable and its cure is still an unmet clinical need. Neoplastic transformation in MM is initiated in the germinal centers (GCs) of secondary lymphoid tissue (SLT) where B cells experience extensive somatic hypermutation induced by follicular dendritic cells (FDCs) and T-cell signals. OBJECTIVE: We reason that secreted protein acidic and rich in cysteine (SPARC), a common stromal motif expressed by FDCs at the origin (SLTs) and the destination (BM) of MM, plays a role in the pathogenesis of MM, and, here, we sought to investigate this role. METHODS: There were 107 BM biopsies from 57 MM patients (taken at different time points) together with 13 control specimens assessed for SPARC gene and protein expression and compared with tonsillar tissues. In addition, regulation of myeloma-promoting genes by SPARC-secreting FDCs was assessed in in vitro GC reactions (GCRs). RESULTS: SPARC gene expression was confirmed in both human primary (BM) and secondary (tonsils) lymphoid tissues, and the expression was significantly higher in the BM. Sparc was detectable in the BM and tonsillar lysates, co-localized with the FDC markers in both tissues, and stimulation of FDCs in vitro induced significantly higher levels of SPARC expression than unstimulated controls. In addition, SPARC inversely correlated with BM PC infiltration, ISS staging, and ECOG performance of the MM patients, and in vitro addition of FDCs to lymphocytes inhibited the expression of several oncogenes associated with malignant transformation of PCs. CONCLUSION: FDC-SPARC inhibits several myelomagenic gene expression and inversely correlates with PC infiltration and MM progression. Therapeutic induction of SPARC expression through combinations of the current MM drugs, repositioning of non-MM drugs, or novel drug discovery could pave the way to better control MM in clinically severe and drug-resistant patients