Entropy Production of Brownian Macromolecules with Inertia

We investigate the nonequilibrium steady-state thermodynamics of single Brownian macromolecules with inertia under feedback control in isothermal ambient fluid. With the control being represented by a velocity-dependent external force, we find such open systems can have a negative entropy production rate and we develop a mesoscopic theory consistent with the second law. We propose an equilibrium condition and define a class of external forces, which includes a transverse Lorentz force, leading to equilibrium.Comment: 10 pages, 1 figur

Improved linkage analysis of Quantitative Trait Loci using bulk segregants unveils a novel determinant of high ethanol tolerance in yeast

Background: Bulk segregant analysis (BSA) coupled to high throughput sequencing is a powerful method to map genomic regions related with phenotypes of interest. It relies on crossing two parents, one inferior and one superior for a trait of interest. Segregants displaying the trait of the superior parent are pooled, the DNA extracted and sequenced. Genomic regions linked to the trait of interest are identified by searching the pool for overrepresented alleles that normally originate from the superior parent. BSA data analysis is non-trivial due to sequencing, alignment and screening errors. Results: To increase the power of the BSA technology and obtain a better distinction between spuriously and truly linked regions, we developed EXPLoRA (EXtraction of over-rePresented aLleles in BSA), an algorithm for BSA data analysis that explicitly models the dependency between neighboring marker sites by exploiting the properties of linkage disequilibrium through a Hidden Markov Model (HMM). Reanalyzing a BSA dataset for high ethanol tolerance in yeast allowed reliably identifying QTLs linked to this phenotype that could not be identified with statistical significance in the original study. Experimental validation of one of the least pronounced linked regions, by identifying its causative gene VPS70, confirmed the potential of our method. Conclusions: EXPLoRA has a performance at least as good as the state-of-the-art and it is robust even at low signal to noise ratio's i.e. when the true linkage signal is diluted by sampling, screening errors or when few segregants are available

W196 and the ß -Hairpin Motif Modulate the Redox Switch of Conformation and the Biomolecular Interaction Network of the Apoptosis-Inducing Factor

The human apoptosis-inducing factor (hAIF) is a moonlight flavoprotein involved in mitochondrial respiratory complex assembly and caspase-independent programmed cell death. These functions might be modulated by its redox-linked structural transition that enables hAIF to act as a NAD(H/+) redox sensor. Upon reduction with NADH, hAIF undergoes a conformational reorganization in two specific insertions - the flexible regulatory C-loop and the 190-202 ß-harpin - promoting protein dimerization and the stabilization of a long-life charge transfer complex (CTC) that modulates its monomer-dimer equilibrium and its protein interaction network in healthy mitochondria. In this regard, here, we investigated the precise function of the ß-hairpin in the AIF conformation landscape related to its redox mechanism, by analyzing the role played by W196, a key residue in the interaction of this motif with the regulatory C-loop. Mutations at W196 decrease the compactness and stability of the oxidized hAIF, indicating that the ß-hairpin and C-loop coupling contribute to protein stability. Kinetic studies complemented with computational simulations reveal that W196 and the ß-hairpin conformation modulate the low efficiency of hAIF as NADH oxidoreductase, contributing to configure its active site in a noncompetent geometry for hydride transfer and to stabilize the CTC state by enhancing the affinity for NAD+. Finally, the ß-hairpin motif contributes to define the conformation of AIF's interaction surfaces with its physiological partners. These findings improve our understanding on the molecular basis of hAIF''s cellular activities, a crucial aspect for clarifying its associated pathological mechanisms and developing new molecular therapies

Mean Field Behavior of Cluster Dynamics

The dynamic behavior of cluster algorithms is analyzed in the classical mean field limit. Rigorous analytical results below $T_c$ establish that the dynamic exponent has the value $z_{sw}=1$ for the Swendsen-Wang algorithm and $z_{uw}=0$ for the Wolff algorithm. An efficient Monte Carlo implementation is introduced, adapted for using these algorithms for fully connected graphs. Extensive simulations both above and below $T_c$ demonstrate scaling and evaluate the finite-size scaling function by means of a rather impressive collapse of the data.Comment: Revtex, 9 pages with 7 figure

A single H/ACA small nucleolar RNA mediates tumor suppression downstream of oncogenic RAS.

Small nucleolar RNAs (snoRNAs) are a diverse group of non-coding RNAs that direct chemical modifications at specific residues on other RNA molecules, primarily on ribosomal RNA (rRNA). SnoRNAs are altered in several cancers; however, their role in cell homeostasis as well as in cellular transformation remains poorly explored. Here, we show that specific subsets of snoRNAs are differentially regulated during the earliest cellular response to oncogenic RASG12V expression. We describe a novel function for one H/ACA snoRNA, SNORA24, which guides two pseudouridine modifications within the small ribosomal subunit, in RAS-induced senescence in vivo. We find that in mouse models, loss of Snora24 cooperates with RASG12V to promote the development of liver cancer that closely resembles human steatohepatitic hepatocellular carcinoma (HCC). From a clinical perspective, we further show that human HCCs with low SNORA24 expression display increased lipid content and are associated with poor patient survival. We next asked whether ribosomes lacking SNORA24-guided pseudouridine modifications on 18S rRNA have alterations in their biophysical properties. Single-molecule Fluorescence Resonance Energy Transfer (FRET) analyses revealed that these ribosomes exhibit perturbations in aminoacyl-transfer RNA (aa-tRNA) selection and altered pre-translocation ribosome complex dynamics. Furthermore, we find that HCC cells lacking SNORA24-guided pseudouridine modifications have increased translational miscoding and stop codon readthrough frequencies. These findings highlight a role for specific snoRNAs in safeguarding against oncogenic insult and demonstrate a functional link between H/ACA snoRNAs regulated by RAS and the biophysical properties of ribosomes in cancer

Cumulants of the three state Potts model and of nonequilibrium models with C3v symmetry

The critical behavior of two-dimensional stochastic lattice gas models with C3v symmetry is analyzed. We study the cumulants of the order parameter for the three state (equilibrium) Potts model and for two irreversible models whose dynamic rules are invariant under the symmetry operations of the point group C3v. By means of extensive numerical analysis of the phase transition we show that irreversibility does not affect the critical behavior of the systems. In particular we find that the Binder reduced fourth order cumulant takes a universal value U* which is the same for the three state Potts model and for the irreversible models. The same universal behavior is observed for the reduced third-order cumulant.Comment: gzipped tar file containing: 1 latex file + 6 eps figure

Critical exponents of a three dimensional O(4) spin model

By Monte Carlo simulation we study the critical exponents governing the transition of the three-dimensional classical O(4) Heisenberg model, which is considered to be in the same universality class as the finite-temperature QCD with massless two flavors. We use the single cluster algorithm and the histogram reweighting technique to obtain observables at the critical temperature. After estimating an accurate value of the inverse critical temperature \Kc=0.9360(1), we make non-perturbative estimates for various critical exponents by finite-size scaling analysis. They are in excellent agreement with those obtained with the $4-\epsilon$ expansion method with errors reduced to about halves of them.Comment: 25 pages with 8 PS figures, LaTeX, UTHEP-28