Familial hypercholesterolemia presenting with multiple nodules of the hands and elbow

Familial hypercholesterolemia (FH) is a common but commonly missed diagnosis. Tendon xanthomas are a physical sign strongly suggestive of FH. Physicians must identify tendon xanthomas, apply validated clinical scoring such as the Dutch Lipid Clinic Network criteria and offer cascade screening. This approach will increase recognition of FH.     

Pivotal role for the ubiquitin Y59-E51 loop in lysine 48 polyubiquitination

Lysine 48 (K48)-polyubiquitination is the predominant mechanism for mediating selective protein degradation, but the underlying molecular basis of selecting ubiquitin (Ub) K48 for linkage-specific chain synthesis remains elusive. Here, we present biochemical, structural, and cell-based evidence demonstrating a pivotal role for the Ub Y59-E51 loop in supporting K48-polyubiquitination. This loop is established by a hydrogen bond between Ub Y59’s hydroxyl group and the backbone amide of Ub E51, as substantiated by NMR spectroscopic analysis. Loop residues Y59 and R54 are specifically required for the receptor activity enabling K48 to attack the donor Ub-E2 thiol ester in reconstituted ubiquitination catalyzed by Skp1-Cullin1-F-box (SCF)^βTrCP E3 ligase and Cdc34 E2-conjugating enzyme. When introduced into mammalian cells, loop-disruptive mutant Ub^R54A/Y59A diminished the production of K48-polyubiquitin chains. Importantly, conditional replacement of human endogenous Ub by Ub^R54A/Y59A or Ub^K48R yielded profound apoptosis at a similar extent, underscoring the global impact of the Ub Y59-E51 loop in cellular K48-polyubiquitination. Finally, disulfide cross-linking revealed interactions between the donor Ub-bound Cdc34 acidic loop and the Ub K48 site, as well as residues within the Y59-E51 loop, suggesting a mechanism in which the Ub Y59-E51 loop helps recruit the E2 acidic loop that aligns the receptor Ub K48 to the donor Ub for catalysis.Central to selective protein turnover by the 26S proteasome is the formation of homotypic lysine 48 (K48)-linked ubiquitin (Ub) chains that tag substrate proteins for degradation (1). Among the most extensively studied systems that produce K48-linked Ub chains is the SCF (Skp1-Cullin1-F-box) E3-directed ubiquitination. SCF is a member of the multisubunit Cullin-RING E3 Ub ligase (CRL) family, the largest of all E3s (2). CRL contains a tandem of a large scaffold protein [Cullin (CUL)] and a RING domain-containing protein (ROC1/Rbx1) that typically associates with an adaptor protein (such as Skp1) in complex with a substrate recognition protein (such as F-box protein). As such, the organization of CRL subunits positions the substrate receptor (such as the F-box protein) within the proximity of ROC1, which recruits an E2-conjugating enzyme that catalyzes the transfer of Ub to a bound substrate. In the SCF reconstitution system, K48-linked polyubiquitin chains on a substrate such as IκBα and β-catenin are produced in a two-step reaction. The E2 UbcH5c deposits the first Ub moiety, forming a substrate–Ub linkage, which is followed by repeated discharge of subsequent Ubs by E2 Cdc34 to form K48-specific Ub chains (3). Human Cdc34 contains a highly conserved charged acidic loop (residues 102–113) that participates in the elongation of K48 chains (4, 5). The current work addresses whether there are determinants on the Ub itself that dictate K48 linkage specificity and, moreover, how Cdc34 might recognize Ub K48.     

Nasal tip modifications

Rhinoplasty remains a challenging art but is now systematized at least in part by recent understanding of the supporting mechanisms and how they may be manipulated to control the nasal tip. Nasal tip control is the key to a successful, aesthetically pleasing, rhinoplasty result with preservation of nasal function.     

The comparative evaluation of the effects of tongue cleaning on salivary levels of mutans streptococci in children

To cite this article:
Int J Dent Hygiene 10 , 2012; 107–112
DOI: 10.1111/j.1601‐5037.2011.00522.x Rupesh S, Winnier JJ, Nayak UA, Rao AP, Reddy V, Peter J. The comparative evaluation of the effects of tongue cleaning on salivary levels of mutans streptococci in children. Abstract: Objectives: The study compared and evaluated the effects of tongue scraping and tongue brushing on salivary mutans streptococci levels in children. Methods: The investigation was a single‐blind, stratified comparison of three parallel groups of children who performed either tongue scraping or tongue brushing along with tooth brushing or only tooth brushing twice daily under professional supervision for a 21‐day period. A total of three saliva samples were taken from each individual, at baseline, on day 10 and on day 21, and colony counts of mutans streptococci were determined. All data were subjected to statistical analysis using Wilcoxon’s signed‐ranks sum test and Mann–Whitney U‐test. Results and conclusions: The results of the present study show that tongue scraping and tongue brushing demonstrated statistically significant reductions in salivary mutans streptococci counts after 10 days and also after 21 days. It was also noted that tongue scraping and tongue brushing were equally effective in reducing colony counts.