Molecular and cellular dynamics of the 26S proteasome

In eukaryotic cells, the ubiquitin-proteasome system serves to remove proteins that are either dysfunctional or no longer needed. The 26S proteasome is a 2.5 MDa multisubunit complex comprising the 20S core particle, where degradation is executed, and one or two regulatory particles which prepare substrates for degradation. Whereas the 20S core particles of several species had been studied extensively by X-ray crystallography, the 26S holocomplex structure had remained elusive for a long time. Recent advances in single-particle cryo-electron microscopy have changed the situation and provided atomic resolution models of this intriguing molecular machine and its dynamics. Besides, cryo-electron tomography enables structural studies in situ, providing molecular resolution images of macromolecules inside pristinely preserved cellular environments. This has greatly contributed to our understanding of proteasome dynamics in the context of cells

Complexity of multivariate polynomial evaluation

We describe a method to evaluate multivariate polynomials over a finite field and discuss its multiplicative complexity

Zitterbewegung of Klein-Gordon particles and its simulation by classical systems

The Klein-Gordon equation is used to calculate the Zitterbewegung (ZB, trembling motion) of spin-zero particles in absence of fields and in the presence of an external magnetic field. Both Hamiltonian and wave formalisms are employed to describe ZB and their results are compared. It is demonstrated that, if one uses wave packets to represent particles, the ZB motion has a decaying behavior. It is also shown that the trembling motion is caused by an interference of two sub-packets composed of positive and negative energy states which propagate with different velocities. In the presence of a magnetic field the quantization of energy spectrum results in many interband frequencies contributing to ZB oscillations and the motion follows a collapse-revival pattern. In the limit of non-relativistic velocities the interband ZB components vanish and the motion is reduced to cyclotron oscillations. The exact dynamics of a charged Klein-Gordon particle in the presence of a magnetic field is described on an operator level. The trembling motion of a KG particle in absence of fields is simulated using a classical model proposed by Morse and Feshbach -- it is shown that a variance of a Gaussian wave packet exhibits ZB oscillations.Comment: 16 pages and 7 figure

Bicyclic imidazolium inhibitors of Gli transcription factor activity

Gli transcription factors within the Hedgehog (Hh) signaling pathway direct key events in mammalian development and promote a number of human cancers. Current therapies for Gli‐driven tumors target Smoothened (SMO), a G protein‐coupled receptor‐like protein that functions upstream in the Hh pathway. Although these drugs can have remarkable clinical efficacy, mutations in SMO and downstream Hh pathway components frequently lead to chemoresistance. In principle, therapies that act at the level of Gli proteins, through direct or indirect mechanisms, would be more efficacious. We therefore conducted a screen of 325,120 compounds for their ability to block the constitutive Gli activity induced by loss of Suppressor of Fused (SUFU), a scaffolding protein that directly inhibits Gli function. Our studies reveal a family of bicyclic imidazolium derivatives that can inhibit Gli‐dependent transcription without affecting the ciliary trafficking or proteolytic processing of these transcription factors. We anticipate that these chemical antagonists will be valuable tools for investigating the mechanisms of Gli regulation and developing new strategies for targeting Gli‐driven cancers

Retinoblastoma and Its Binding Partner MSI1 Control Imprinting in Arabidopsis

Parental genomic imprinting causes preferential expression of one of the two parental alleles. In mammals, differential sex-dependent deposition of silencing DNA methylation marks during gametogenesis initiates a new cycle of imprinting. Parental genomic imprinting has been detected in plants and relies on DNA methylation by the methyltransferase MET1. However, in contrast to mammals, plant imprints are created by differential removal of silencing marks during gametogenesis. In Arabidopsis, DNA demethylation is mediated by the DNA glycosylase DEMETER (DME) causing activation of imprinted genes at the end of female gametogenesis. On the basis of genetic interactions, we show that in addition to DME, the plant homologs of the human Retinoblastoma (Rb) and its binding partner RbAp48 are required for the activation of the imprinted genes FIS2 and FWA. This Rb-dependent activation is mediated by direct transcriptional repression of MET1 during female gametogenesis. We have thus identified a new mechanism required for imprinting establishment, outlining a new role for the Retinoblastoma pathway, which may be conserved in mammals

Comment on ``the Klein-Gordon Oscillator''

The different ways of description of the $S=0$ particle with oscillator-like interaction are considered. The results are in conformity with the previous paper of S. Bruce and P. Minning.Comment: LaTeX file, 5p

Novel method to rescue a lethal phenotype through integration of target gene onto the X-chromosome.

The loss-of-function mutations of serine protease inhibitor, Kazal type 1 (SPINK1) gene are associated with human chronic pancreatitis, but the underlying mechanisms remain unknown. We previously reported that mice lacking Spink3, the murine homologue of human SPINK1, die perinatally due to massive pancreatic acinar cell death, precluding investigation of the effects of SPINK1 deficiency. To circumvent perinatal lethality, we have developed a novel method to integrate human SPINK1 gene on the X chromosome using Cre-loxP technology and thus generated transgenic mice termed "X-SPINK1". Consistent with the fact that one of the two X chromosomes is randomly inactivated, X-SPINK1 mice exhibit mosaic pattern of SPINK1 expression. Crossing of X-SPINK1 mice with Spink3+/- mice rescued perinatal lethality, but the resulting Spink3-/-;XXSPINK1 mice developed spontaneous pancreatitis characterized by chronic inflammation and fibrosis. The results show that mice lacking a gene essential for cell survival can be rescued by expressing this gene on the X chromosome. The Spink3-/-;XXSPINK1 mice, in which this method has been applied to partially restore SPINK1 function, present a novel genetic model of chronic pancreatitis

Complex sequencing rules of birdsong can be explained by simple hidden Markov processes

Complex sequencing rules observed in birdsongs provide an opportunity to investigate the neural mechanism for generating complex sequential behaviors. To relate the findings from studying birdsongs to other sequential behaviors, it is crucial to characterize the statistical properties of the sequencing rules in birdsongs. However, the properties of the sequencing rules in birdsongs have not yet been fully addressed. In this study, we investigate the statistical propertiesof the complex birdsong of the Bengalese finch (Lonchura striata var. domestica). Based on manual-annotated syllable sequences, we first show that there are significant higher-order context dependencies in Bengalese finch songs, that is, which syllable appears next depends on more than one previous syllable. This property is shared with other complex sequential behaviors. We then analyze acoustic features of the song and show that higher-order context dependencies can be explained using first-order hidden state transition dynamics with redundant hidden states. This model corresponds to hidden Markov models (HMMs), well known statistical models with a large range of application for time series modeling. The song annotation with these models with first-order hidden state dynamics agreed well with manual annotation, the score was comparable to that of a second-order HMM, and surpassed the zeroth-order model (the Gaussian mixture model (GMM)), which does not use context information. Our results imply that the hierarchical representation with hidden state dynamics may underlie the neural implementation for generating complex sequences with higher-order dependencies