Structural analysis of B-Box 2 from MuRF1: identification of a novel self-association pattern in a RING-like fold

The B-box motif is the defining feature of the TRIM family of proteins, characterized by a RING finger-B-box-coiled coil tripartite fold. We have elucidated the crystal structure of B-box 2 (B2) from MuRF1, a TRIM protein that supports a wide variety of protein interactions in the sarcomere and regulates the trophic state of striated muscle tissue. MuRF1 B2 coordinates two zinc ions through a cross-brace alpha/beta-topology typical of members of the RING finger superfamily. However, it self-associates into dimers with high affinity. The dimerization pattern is mediated by the helical component of this fold and is unique among RING-like folds. This B2 reveals a long shallow groove that encircles the C-terminal metal binding site ZnII and appears as the defining protein-protein interaction feature of this domain. A cluster of conserved hydrophobic residues in this groove and, in particular, a highly conserved aromatic residue (Y133 in MuRF1 B2) is likely to be central to this role. We expect these findings to aid the future exploration of the cellular function and therapeutic potential of MuRF1.

Cystatin C is independently associated with total and cardiovascular mortality in individuals undergoing coronary angiography. The Ludwigshafen Risk and Cardiovascular Health (LURIC) study.

AIMS Cystatin C is a well established marker of kidney function. There is evidence that cystatin C concentrations are also associated with mortality. The present analysis prospectively evaluated the associations of cystatin C with all-cause and cardiovascular (CV) mortality in a well-characterized cohort of persons undergoing angiography, but without overt renal insufficiency. METHODS Cystatin C was available in 2998 persons (mean age: 62.7 ± 10.5 years; 30.3% women). Of those 2346 suffered from coronary artery disease (CAD) and 652 (controls) did not. Creatinine (mean ± SD: 83.1 ± 47.8 vs. 74.1 ± 24.7 μmol/L, p = 0.036) but not Cystatin C (mean ± SD: 1.02 ± 0.44 vs. 0.92 ± 0.26 mg/L, p = 0.065) was significantly higher in patients with CAD. After a median follow-up of 9.9 years, in total 898 (30%) deaths occurred, 554 (18.5%) due to CV disease and 326 (10.9%) due to non-CV causes. Multivariable-adjusted Cox analysis (adjusting for eGFR and established cardiovascular risk factors, lipid lowering therapy, angiographic coronary artery disease, and C-reactive protein) revealed that patients in the highest cystatin C quartile were at an increased risk for all-cause (hazard ratio (HR) 1.93, 95% CI 1.50-2.48) and CV mortality (HR 2.05 95% CI 1.48-2.84) compared to those in the lowest quartile. The addition of cystatin C to a model consisting of established cardiovascular risk factors increased the area under the receiver-operating characteristic curve for CV and all-cause mortality, but the difference was statistically not significant. However, reclassification analysis revealed significant improvement by addition of cystatin C for CV and all-cause mortality (p < 0.001), respectively. CONCLUSION The concentration of cystatin C is strongly associated with long-term all-cause and cardiovascular mortality in patients referred to coronary angiography, irrespective of creatinine-based renal function.

Efficacy of lead-in silibinin and subsequent triple therapy in difficult-to-treat HIV/hepatitis C virus-coinfected patients

OBJECTIVES: The efficacy of current hepatitis C virus (HCV) triple therapy, including a protease inhibitor, is limited in HIV/HCV-coinfected patients with advanced liver fibrosis and nonresponse to previous peginterferon-ribavirin. These patients have a low chance (only 30%) of achieving a sustained virological response (SVR) during triple therapy and cannot wait for next-generation anti-HCV drugs. In a pilot study, we investigated the efficacy of a lead-in therapy with silibinin before triple therapy in difficult-to-treat patients. METHODS: Inclusion criteria were HIV/HCV coinfection with advanced liver fibrosis and documented failure of previous peginterferon-ribavirin treatment. Intervention was lead-in therapy with intravenous silibinin 20 mg/kg/day for 14 days. Subsequently, peginterferon-ribavirin combined with telaprevir was initiated for 12 weeks, followed by peginterferon-ribavirin dual therapy until week 48 after initiation of triple therapy. The outcome measurements were HCV RNA after silibinin lead-in, at weeks 2, 4 and 12 of triple therapy, and SVR at week 24 after the end of treatment. RESULTS: We examined six HIV/HCV-coinfected patients (four infected with genotype 1a). All had fibrosis grade METAVIR ≥F3 and were on fully suppressive antiretroviral therapy. Mean HCV RNA decline after silibinin therapy was 2.6 log10 IU/mL (range 2-3 log10 IU/mL). Five of the six patients were virologically suppressed at weeks 2 and 4, and all six at week 12 of triple therapy. One experienced a viral breakthrough thereafter. Four of five patients (80%) showed an SVR 24. One patient had an SVR 12 but has not yet reached week 24. CONCLUSIONS: A lead-in with silibinin before triple therapy is highly effective and increases the probability of HCV treatment success in difficult-to-treat HIV/HCV-coinfected patients with advanced liver fibrosis and previous failure of peginterferon-ribavirin.

Moses und Christus : oder üb. d. innern Werth u. d. wahrscheinl. Folgen d. Sendschreibens einiger Hausväter jüdischer Religion an Herrn Probst Teller u. dessen darauf ertheilte Antwort

[Benjamin Gottlob Gerlach]

Ueberzeugung eines Israeliten, gegenüber dem Proselytenthum : Erwiederung auf d. Schrift d. Herrn Dr. W. B. Fränkel "Das Bekenntnis d. Proselyten. : d. Unglück d. Juden u. ihre Emanzipation in Deutschland"

von L. H. Loewenstein

Offene Antwort auf den offenen Brief des Herrn Rabbiners S. R. Hirsch an Herrn Rabbiner S. B.

von X.

Die Verjudung Deutschlands und der Weg zur Rettung : noch einmal ein Wort für u. wider "W. Marr: Der Sieg d. Judenthums üb. d. Germanenthum"

von Paul Köhler

Das Ceremonialgesetz im Messiasreich : als Vorläufer einer grössern Schrift üb. d. religiöse Reform d. Judenthums ; nebst e. krit. Abh. üb. d. Aufsatz: Reformbestrebungen u. Emancipation in d. Zeitschrift f. d. Interessen d. Judenthums

von Sam. Holdheim

Betrachtungen üb. die den Mosaismus u. die Neologie d. Rabbinen betr. königl. bayer. Ministerial-Entschliessung

von [Josef] Aub

Widerlegungen, ein Dialog üb. Herrn Hirsch's Mittheilungen aus Naphtali's Briefwechsel

hrsg. von [Josef] Aub

Vorschläge zur Verbesserung des israelitischen Gottesdienstes : nebst e. Predigt über die Sidra Reeh 5 B. M. XI. 26 - XVI. 18. als Probe aus e. größeren Samml.

seinen Glaubensgenossen vorgelegt von A. Bock

"Was soll aus den Juden werden?" : Eine Abhandlung üb. d. Judenfrage

von Leo N. Levi. Aus d. Engl. übers. von H. Berliner

Anklagerede gehalten von Camill Velter in der Sitzung des Zuchtpolizeigerichtes am 12. März 1889 in Sachen des öffentlichen Ministeriums gegen die Redaktion des "Luxemburger Wort" wegen Beleidigung der jüdischen Religion und ihrer Bekenner : nebst e. Vorw. üb. d. Geschichte u. d. Verlauf d. Prozesses

Autor. Übers. d. französ. Originaltextes

Vom jüdischen Wesen : Vortr., geh. im Isr. Humanitätsverein "Bohemia" B'nai B'rith in Prag am 6. Nov. 1915

von Emil Spiegel