The mismatch repair system protects against intergenerational GAA repeat instability in a Friedreich ataxia mouse model

Copyright @ 2012 Elsevier. The article can be accessed from the link below.This article has been made available through the Brunel Open Access Publishing Fund.Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disorder caused by a dynamic GAA repeat expansion mutation within intron 1 of the FXN gene. Studies of mouse models for other trinucleotide repeat (TNR) disorders have revealed an important role of mismatch repair (MMR) proteins in TNR instability. To explore the potential role of MMR proteins on intergenerational GAA repeat instability in FRDA, we have analyzed the transmission of unstable GAA repeat expansions from FXN transgenic mice which have been crossed with mice that are deficient for Msh2, Msh3, Msh6 or Pms2. We find in all cases that absence of parental MMR protein not only maintains transmission of GAA expansions and contractions, but also increases GAA repeat mutability (expansions and/or contractions) in the offspring. This indicates that Msh2, Msh3, Msh6 and Pms2 proteins are not the cause of intergenerational GAA expansions or contractions, but act in their canonical MMR capacity to protect against GAA repeat instability. We further identified differential modes of action for the four MMR proteins. Thus, Msh2 and Msh3 protect against GAA repeat contractions, while Msh6 protects against both GAA repeat expansions and contractions, and Pms2 protects against GAA repeat expansions and also promotes contractions. Furthermore, we detected enhanced occupancy of Msh2 and Msh3 proteins downstream of the FXN expanded GAA repeat, suggesting a model in which Msh2/3 dimers are recruited to this region to repair mismatches that would otherwise produce intergenerational GAA contractions. These findings reveal substantial differences in the intergenerational dynamics of expanded GAA repeat sequences compared with expanded CAG/CTG repeats, where Msh2 and Msh3 are thought to actively promote repeat expansions.This study is funded under European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement number 242193/EFACTS. This article is made available through the Brunel Open Access Publishing Fund

Revisiting the Female Germline and Its Expanding Toolbox

The Arabidopsis thaliana ovule arises as a female reproductive organ composed solely of somatic diploid cells. Among them, one cell will acquire a unique identity and initiate female germline development. In this review we explore the complex network that facilitates differentiation of this single cell, and consider how it becomes committed to a distinct developmental program. We highlight recent progress towards understanding the role of intercellular communication, cell competency, and cell-cycle regulation in the ovule primordium, and we discuss the possibility that distinct pathways restrict germline development at different stages. Importantly, these recent findings suggest a renaissance in plant ovule research, restoring the female germline as an attractive model to study cell communication and cell fate establishment in multicellular organs

Traveling waves for a model of the Belousov-Zhabotinsky reaction

Following J.D. Murray, we consider a system of two differential equations that models traveling fronts in the Noyes-Field theory of the Belousov-Zhabotinsky (BZ) chemical reaction. We are also interested in the situation when the system incorporates a delay $h\geq 0$. As we show, the BZ system has a dual character: it is monostable when its key parameter $r \in (0,1]$ and it is bistable when $r >1$. For $h=0, r\not=1$, and for each admissible wave speed, we prove the uniqueness of monotone wavefronts. Next, a concept of regular super-solutions is introduced as a main tool for generating new comparison solutions for the BZ system. This allows to improve all previously known upper estimations for the minimal speed of propagation in the BZ system, independently whether it is monostable, bistable, delayed or not. Special attention is given to the critical case $r=1$ which to some extent resembles to the Zeldovich equation.Comment: 23 pages, to appear in the Journal of Differential Equation

Single-cell transcriptional profiling reveals cellular diversity and intercommunication in the mouse heart

Characterization of the cardiac cellulome, the network of cells that form the heart, is essential for understanding cardiac development and normal organ function and for formulating precise therapeutic strategies to combat heart disease. Recent studies have reshaped our understanding of cardiac cellular composition and highlighted important functional roles for non-myocyte cell types. In this study, we characterized single-cell transcriptional profiles of the murine non-myocyte cardiac cellular landscape using single-cell RNA sequencing (scRNA-seq). Detailed molecular analyses revealed the diversity of the cardiac cellulome and facilitated the development of techniques to isolate understudied cardiac cell populations, such as mural cells and glia. Our analyses also revealed extensive networks of intercellular communication and suggested prevalent sexual dimorphism in gene expression in the heart. This study offers insights into the structure and function of the mammalian cardiac cellulome and provides an important resource that will stimulate studies in cardiac cell biology

Human annexin A6 interacts with influenza a virus protein M2 and negatively modulates infection

Copyright © 2012, American Society for Microbiology. All Rights ReservedThe influenza A virus M2 ion channel protein has the longest cytoplasmic tail (CT) among the three viral envelope proteins and is well conserved between different viral strains. It is accessible to the host cellular machinery after fusion with the endosomal membrane and during the trafficking, assembly, and budding processes. We hypothesized that identification of host cellular interactants of M2 CT could help us to better understand the molecular mechanisms regulating the M2-dependent stages of the virus life cycle. Using yeast two-hybrid screening with M2 CT as bait, a novel interaction with the human annexin A6 (AnxA6) protein was identified, and their physical interaction was confirmed by coimmunoprecipitation assay and a colocalization study of virus-infected human cells. We found that small interfering RNA (siRNA)-mediated knockdown of AnxA6 expression significantly increased virus production, while its overexpression could reduce the titer of virus progeny, suggesting a negative regulatory role for AnxA6 during influenza A virus infection. Further characterization revealed that AnxA6 depletion or overexpression had no effect on the early stages of the virus life cycle or on viral RNA replication but impaired the release of progeny virus, as suggested by delayed or defective budding events observed at the plasma membrane of virus-infected cells by transmission electron microscopy. Collectively, this work identifies AnxA6 as a novel cellular regulator that targets and impairs the virus budding and release stages of the influenza A virus life cycle.This work was supported by the Research Fund for the Control of Infectious Disease (project 09080892) of the Hong Kong Government, the Area of Excellence Scheme of the University Grants Committee (grant AoE/M-12/-06 of the Hong Kong Special Administrative Region, China), the French Ministry of Health, the RESPARI Pasteur Network

Anomalous quartic gauge boson couplings at hadron colliders

We analyze the potential of the Fermilab Tevatron and CERN Large Hadron Collider (LHC) to study anomalous quartic vector--boson interactions (photon photon Z Z) and (photon photon W+ W-). Working in the framework of SU(2)_L X U(1)_Y chiral Lagrangians, we study the production of photons pairs accompanied by (e+e-), (e nu), and jet pairs to impose bounds on these new couplings, taking into account the unitarity constraints. We compare our findings with the indirect limits coming from precision electroweak measurements as well as with presently available direct searches at LEPII. We show that the Tevatron Run II can provide limits on these quartic limits which are of the same order of magnitude as the existing bounds from LEPII searches. LHC will be able to tighten considerably the direct constraints on these possible new interactions, leading to more stringent limits than the presently available indirect ones

Robust determination of the Higgs couplings: Power to the data

We study the indirect effects of new physics on the phenomenology of the recently discovered "Higgs-like" particle. In a model-independent framework these effects can be parametrized in terms of an effective Lagrangian at the electroweak scale. In a theory in which the S U ( 2 ) L × U ( 1 ) Y gauge symmetry is linearly realized they appear at lowest order as dimension-six operators, containing all the standard model fields including the light scalar doublet, with unknown coefficients. We discuss the choice of operator basis which allows us to make better use of all the available data to determine the coefficients of the new operators. We illustrate our present knowledge of those by performing a global five-parameter fit to the existing data which allows simultaneous determination of the Higgs couplings to gluons, electroweak gauge bosons, bottom quarks, and tau leptons. We find that for all scenarios considered the standard model predictions for each individual Higgs coupling and observable are within the corresponding 90% C.L. allowed range, the only exception being the Higgs branching ratio into two photons for the scenario with standard couplings of the Higgs to fermions. We finish by commenting on the implications of the results for unitarity of processes at higher energies

Constraining anomalous Higgs boson interactions

The recently announced Higgs boson discovery marks the dawn of the direct probing of the electroweak symmetry breaking sector. Sorting out the dynamics responsible for electroweak symmetry breaking now requires probing the Higgs boson interactions and searching for additional states connected to this sector. In this work, we analyze the constraints on Higgs boson couplings to the standard model gauge bosons using the available data from Tevatron and LHC. We work in a model-independent framework expressing the departure of the Higgs boson couplings to gauge bosons by dimension-six operators. This allows for independent modifications of its couplings to gluons, photons, and weak gauge bosons while still preserving the Standard Model (SM) gauge invariance. Our results indicate that best overall agreement with data is obtained if the cross section of Higgs boson production via gluon fusion is suppressed with respect to its SM value and the Higgs boson branching ratio into two photons is enhanced, while keeping the production and decays associated to couplings to weak gauge bosons close to their SM prediction

Deciphering the spin of new resonances in Higgsless models

We study the potential of the CERN large hadron collider to probe the spin of new massive vector boson resonances predicted by Higgsless models. We consider its production via weak boson fusion which relies only on the coupling between the new resonances and the weak gauge bosons. We show that the large hadron collider will be able to unravel the spin of the particles associated with the partial restoration of unitarity in vector boson scattering for integrated luminosities of 150 - 560     fb − 1 , depending on the new state mass and on the method used in the analyses

Determining Triple Gauge Boson Couplings from Higgs Data

In the framework of effective Lagrangians with the S U ( 2 ) L × U ( 1 ) Y symmetry linearly realized, modifications of the couplings of the Higgs field to the electroweak gauge bosons are related to anomalous triple gauge couplings (TGCs). Here, we show that the analysis of the latest Higgs boson production data at the LHC and Tevatron give rise to strong bounds on TGCs that are complementary to those from direct TGC analysis. We present the constraints on TGCs obtained by combining all available data on direct TGC studies and on Higgs production analysis