Supramolecular organization of the human N-BAR domain in shaping the sarcolemma membrane

This is the final version of the article. Available from Elsevier via the DOI in this record.The 30 kDa N-BAR domain of the human Bin1 protein is essential for the generation of skeletal muscle T-tubules. By electron cryo-microscopy and electron cryo-tomography with a direct electron detector, we found that Bin1-N-BAR domains assemble into scaffolds of low long-range order that form flexible membrane tubules. The diameter of the tubules closely matches the curved shape of the N-BAR domain, which depends on the composition of the target membrane. These insights are fundamental to our understanding of T-tubule formation and function in human skeletal muscle.This work was supported by grants from the Deutsche Forschungsgemeinschaft (GRK 1026, SFB610) (A.A., T.G., J.B.), the BMBF ZIK program (A.M., J.B.), the European Regional Development Fund of the European Commission (A.M., T.G.: EFRE 1241 12 0001), and the state Sachsen-Anhalt (A.M., T.G., J.B.)

A Cu2+ complex induces the aggregation of human papillomavirus oncoprotein E6 and stabilizes p53.

Papillomavirus oncoprotein E6 is a critical factor in the modulation of cervical cancer in humans. At the molecular level, formation of the E6-E6AP-p53 ternary complex, which directs p53's degradation, is the key instigator of cancer transforming properties. Herein, a Cu2+ anthracenyl-terpyridine complex is described which specifically induces the aggregation of E6 in vitro and in cultured cells. For a hijacking mechanism, both E6 and E6AP are required for p53 ubiquitination and degradation. The Cu2+ complex interacts with E6 at the E6AP and p53 binding sites. We show that E6 function is suppressed by aggregation, rendering it incapable of hijacking p53 and thus increasing its cellular level. Therapeutic treatments of cervical cancer are currently unavailable to infected individuals. We anticipate that this Cu2+ complex might open up a new therapeutic avenue for the design and development of new chemical entities for the diagnosis and treatment of HPV-induced cancers

An Approach for Hierachical System Level Diagnosis of Massively Parallel Computers Combined with a Simulation-based Method for Dependability Analysis

The primary focus in the analysis of massively parallel supercomputers has traditionally been on their performance. However, their complex network topologies, large number of processors, and sophisticated system software can make them very unreliable. If every failure of one of the many components of a massively parallel computer could shut down the machine, the machine would be useless. Therefore fault tolerance is required. The basis of effective m~hanisms for fault tolerance is an efficient diagnosis. This paper deals with concurrent and hierarchical system level diagnosis for a particular massively parallel architecture and with a sinaulation-based method to validate the proposed diagnosis algorithm. The diagnosis algorithm is presented and we describe a simulation-based method to test and verify the algorithms for fault tolerance already during the design phase of the target machine

Recent Developments in Algorithmic Teaching

Abstract. The present paper surveys recent developments in algorith-mic teaching. First, the traditional teaching dimension model is recalled. Starting from the observation that the teaching dimension model some-times leads to counterintuitive results, recently developed approaches are presented. Here, main emphasis is put on the following aspects derived from human teaching/learning behavior: the order in which examples are presented should matter; teaching should become harder when the memory size of the learners decreases; teaching should become easier if the learners provide feedback; and it should be possible to teach infinite concepts and/or finite and infinite concept classes. Recent developments in the algorithmic teaching achieving (some) of these aspects are presented and compared.

Mitochondrial Physiology and Gene Expression Analyses Reveal Metabolic and Translational Dysregulation in Oocyte-Induced Somatic Nuclear Reprogramming

While reprogramming a foreign nucleus after somatic cell nuclear transfer (SCNT), the enucleated oocyte (ooplasm) must signal that biomass and cellular requirements changed compared to the nucleus donor cell. Using cells expressing nuclear-encoded but mitochondria-targeted EGFP, a strategy was developed to directly distinguish maternal and embryonic products, testing ooplasm demands on transcriptional and post-transcriptional activity during reprogramming. Specifically, we compared transcript and protein levels for EGFP and other products in pre-implantation SCNT embryos, side-by-side to fertilized controls (embryos produced from the same oocyte pool, by intracytoplasmic injection of sperm containing the EGFP transgene). We observed that while EGFP transcript abundance is not different, protein levels are significantly lower in SCNT compared to fertilized blastocysts. This was not observed for Gapdh and Actb, whose protein reflected mRNA. This transcript-protein relationship indicates that the somatic nucleus can keep up with ooplasm transcript demands, whilst transcription and translation mismatch occurs after SCNT for certain mRNAs. We further detected metabolic disturbances after SCNT, suggesting a place among forces regulating post-transcriptional changes during reprogramming. Our observations ascribe oocyte-induced reprogramming with previously unsuspected regulatory dimensions, in that presence of functional proteins may no longer be inferred from mRNA, but rather depend on post-transcriptional regulation possibly modulated through metabolism