Kadanoff-Baym approach to quantum transport through interacting nanoscale systems: From the transient to the steady-state regime

We propose a time-dependent many-body approach to study the short-time dynamics of correlated electrons in quantum transport through nanoscale systems contacted to metallic leads. This approach is based on the time-propagation of the Kadanoff-Baym equations for the nonequilibrium many-body Green's function of open and interacting systems out of equilibrium. An important feature of the method is that it takes full account of electronic correlations and embedding effects in the presence of time-dependent external fields, while at the same time satisfying the charge conservation law. The method further extends the Meir-Wingreen formula to the time domain for initially correlated states. We study the electron dynamics of a correlated quantum wire attached to two-dimensional leads exposed to a sudden switch-on of a bias voltage using conserving many-body approximations at Hartree-Fock, second Born and GW level. We obtain detailed results for the transient currents, dipole moments, spectral functions, charging times, and the many-body screening of the quantum wire as well as for the time-dependent density pattern in the leads, and we show how the time-dependence of these observables provides a wealth of information on the level structure of the quantum wire out of equilibrium. For moderate interaction strenghts the 2B and GW results are in excellent agreement at all times. We find that many-body effects beyond the Hartree-Fock approximation have a large effect on the qualitative behavior of the system and lead to a bias dependent gap closing and quasiparticle broadening, shortening of the transient times and washing out of the step features in the current-voltage curves.Comment: 16 pages, 14 figure

Adiabatic non-equilibrium steady states in the partition free approach

Consider a small sample coupled to a finite number of leads, and assume that the total (continuous) system is at thermal equilibrium in the remote past. We construct a non-equilibrium steady state (NESS) by adiabatically turning on an electrical bias between the leads. The main mathematical challenge is to show that certain adiabatic wave operators exist, and to identify their strong limit when the adiabatic parameter tends to zero. Our NESS is different from, though closely related with the NESS provided by the Jak{\v s}i{\'c}-Pillet-Ruelle approach. Thus we partly settle a question asked by Caroli {\it et al} in 1971 regarding the (non)equivalence between the partitioned and partition-free approaches

Genomic insights into cancer-associated aberrant CpG island hypermethylation

Carcinogenesis is thought to occur through a combination of mutational and epimutational events that disrupt key pathways regulating cellular growth and division. The DNA methylomes of cancer cells can exhibit two striking differences from normal cells; a global reduction of DNA methylation levels and the aberrant hypermethylation of some sequences, particularly CpG islands (CGIs). This aberrant hypermethylation is often invoked as a mechanism causing the transcriptional inactivation of tumour suppressor genes that directly drives the carcinogenic process. Here, we review our current understanding of this phenomenon, focusing on how global analysis of cancer methylomes indicates that most affected CGI genes are already silenced prior to aberrant hypermethylation during cancer development. We also discuss how genome-scale analyses of both normal and cancer cells have refined our understanding of the elusive mechanism(s) that may underpin aberrant CGI hypermethylation

The effect of prolyl oligopeptidase inhibitors on alpha-synuclein aggregation and autophagy cannot be predicted by their inhibitory efficacy

Previous studies have shown that prolyl oligopeptidase (PREP) negatively regulates autophagy and increases the aggregation of alpha-synuclein (alpha Syn), linking it to the pathophysiology of Parkinson's disease. Our earlier results have revealed that the potent small molecular PREP inhibitor KYP-2047 is able to increase autophagy and decrease dimerization of alpha Syn but other PREP inhibitors have not been systematically studied for these two protein-protein interaction mediated biological functions of PREP. In this study, we characterized these effects for 12 known PREP inhibitors with IC50-values ranging from 0.2 nM to 1010 nM. We used protein-fragment complementation assay (PCA) to assess alpha Syn dimerization and Western Blot of microtubule-associated protein light chain 3B II (LC3B-II) and a GFP-LC3-RFP expressing cell line to study autophagy. In addition, we tested selected compounds in a cell-free alpha Syn aggregation assay, native gel electrophoresis, and determined the compound concentration inside the cell by LC-MS. We found that inhibition of the proteolytic activity of PREP did not predict decreased alpha Syn dimerization or increased autophagy, and we also confirmed that this result did not simply reflect concentration differences of the compounds inside the cell. Thus, PREP ligands regulate the effect of PREP on autophagy and alpha Syn aggregation through a conformational stabilization of the enzyme that is not equivalent to inhibiting its proteolytic activity.Peer reviewe

Canine MPV17 truncation without clinical manifestations

Mitochondrial DNA depletion syndromes (MDS) are often serious autosomal recessively inherited disorders characterized by tissue-specific mtDNA copy number reduction. Many genes, including MPV17, are associated with the hepatocerebral form of MDS. MPV17 encodes for a mitochondrial inner membrane protein with a poorly characterized function. Several MPV17 mutations have been reported in association with a heterogeneous group of early-onset manifestations, including liver disease and neurological problems. Mpv17-deficient mice present renal and hearing defects. We describe here a MPV17 truncation mutation in dogs. We found a 1-bp insertion in exon 4 of the MPV17 gene, resulting in a frameshift and early truncation of the encoded protein. The mutation halves MPV17 expression in the lymphocytes of the homozygous dogs and the truncated protein is not translated in transfected cells. The insertion mutation is recurrent and exists in many unrelated breeds, although is highly enriched in the Boxer breed. Unexpectedly, despite the truncation of MPV17, we could not find any common phenotypes in the genetically affected dogs. The lack of observable phenotype could be due to a late onset, mild symptoms or potential tissue-specific compensatory mechanisms. This study suggests species-specific differences in the manifestation of the MPV17 defects and establishes a novel large animal model to further study MPV17 function and role in mitochondrial biology.Peer reviewe

The metalloprotease PrtV from Vibrio cholerae Purification and properties

The Vibrio metalloprotease PrtV was purified from the culture supernatant of a Vibrio cholerae derivative that is deficient in several other secreted peptidases, including the otherwise abundant hemagglutinin/protease HapA. The PrtV is synthesized as a 102 kDa protein, but undergoes several N- and C-terminal processing steps during V. cholerae envelope translocation and prolonged incubation. Purified V. cholerae PrtV protease forms of 81 or 73 kDa were stabilized by calcium ions. Removal of calcium resulted in further rapid autoproteolysis. The two major products of autoproteolysis of the PrtV protease were approximately 37 and 18 kDa and could not be separated under non-denaturing conditions, indicating they are interacting domains. In an assay using cultured cells of the human intestinal cell line HCT8, the PrtV protein showed a cytotoxic effect leading to cell death. Using human blood plasma as a source of potential substrates of mammalian origin for the PrtV protease, we found that the extracellular matrix components fibronectin and fibrinogen were degraded by the enzyme. Additional tests with individual protein substrates revealed that plasminogen was also a possible target for the PrtV protease

Convergence of Mutation and Epigenetic Alterations Identifies Common Genes in Cancer That Predict for Poor Prognosis

Stephen Baylin and colleagues show that a combined genetic and epigenetic analysis of breast and colon cancers identifies a number of clinically significant genes targeted by multiple modes of inactivation

Mice Deficient in Transmembrane Prostatic Acid Phosphatase Display Increased GABAergic Transmission and Neurological Alterations

Peer reviewe

Plasminogen binding and activation at the breast cancer cell surface: the integral role of urokinase activity

INTRODUCTION: The regulation of extracellular proteolytic activity via the plasminogen activation system is complex, involving numerous activators, inhibitors, and receptors. Previous studies on monocytic and colon cell lines suggest that plasmin pre-treatment can increase plasminogen binding, allowing the active enzyme to generate binding sites for its precursor. Other studies have shown the importance of pre-formed receptors such as annexin II heterotetramer. However, few studies have used techniques that exclusively characterise cell-surface events and these mechanisms have not been investigated at the breast cancer cell surface. METHODS: We have studied plasminogen binding to MCF-7 in which urokinase plasminogen activator receptor (uPAR) levels were upregulated by PMA (12-O-tetradecanoylphorbol-13-acetate) stimulation, allowing flexible and transient modulation of cell-surface uPA. Similar experiments were also performed using MDA-MB-231 cells, which overexpress uPAR/uPA endogenously. Using techniques that preserve cell integrity, we characterise the role of uPA as both a plasminogen receptor and activator and quantify the relative contribution of pre-formed and cryptic plasminogen receptors to plasminogen binding. RESULTS: Cell-surface plasminogen binding was significantly enhanced in the presence of elevated levels of uPA in an activity-dependent manner and was greatly attenuated in the presence of the plasmin inhibitor aprotinin. Pre-formed receptors were also found to contribute to increased plasminogen binding after PMA stimulation and to co-localise with uPA/uPAR and plasminogen. Nevertheless, a relatively modest increase in plasminogen-binding capacity coupled with an increase in uPA led to a dramatic increase in the proteolytic capacity of these cells. CONCLUSION: We show that the majority of lysine-dependent plasminogen binding to breast cancer cells is ultimately regulated by plasmin activity and is dependent on the presence of significant levels of active uPA. The existence of a proteolytic positive feedback loop in plasminogen activation has profound implications for the ability of breast cancer cells expressing high amounts of uPA to accumulate a large proteolytic capacity at the cell surface, thereby conferring invasive potential

Multiagent chemopreventive agent combinations

Cancer chemoprevention is a new discipline whose foundation rests upon epidemiologic evidence suggesting that dietary components such as beta-carotene, vitamin E, calcium and selenium may be inhibitors of carcinogenesis. Over the last decade, as molecular and biochemical mechanisms of the carcinogenesis process have been elucidated, the rationale of combining chemopreventive agents to target multiple pathways has strengthened. The process of identifying potential synergistic combinations of chemoprevention agents should be based upon a systematic process of preclinical development in vitro followed by testing in animal models of carcinogenesis. Surrogates of anticarcinogenesis effects might include biochemical, molecular and pathologic assessment of tissue from animal carcinogenesis models. If evidence of chemopreventive effect is found in animal models, systematic studies in humans are indicated. These studies should include a careful Phase I trial to describe optimal chemoprevention doses for all agents being tested in combination followed by Phase II trials to assess efficacy upon carcinogenesis biological and pathological surrogates. J. Cell. Biochem. Suppl. 34:121–124, 2000. © 2000 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/34899/1/19_ftp.pd