Base pair opening within B-DNA: free energy pathways for GC and AT pairs from umbrella sampling simulations.

The conformational pathways and the free energy variations for base opening into the major and minor grooves of a B-DNA duplex are studied using umbrella sampling molecular dynamics simulations. We compare both GC and AT base pair opening within a double-stranded d(GAGAGAGAGAGAG). d(CTCTCTCTCTCTC) oligomer, and we are also able to study the impact of opening on the conformational and dynamic properties of DNA and on the surrounding solvent. The results indicate a two-stage opening process with an initial coupling of the movements of the bases within the perturbed base pair. Major and minor groove pathways are energetically comparable in the case of the pyrimidine bases, but the major groove pathway is favored for the larger purine bases. Base opening is coupled to changes in specific backbone dihedrals and certain helical distortions, including untwisting and bending, although all these effects are dependent on the particular base involved. Partial opening also leads to well defined water bridging sites, which may play a role in stabilizing the perturbed base pairs

Unifying gauge couplings at the string scale

Using the current precision electroweak data, we look for the minimal particle content which is necessary to add to the standard model in order to have a complete unification of gauge couplings and gravity at the weakly coupled heterotic string scale. We find that the addition of a vector-like fermion at an intermediate scale and a non-standard hypercharge normalization are in general sufficient to achieve this goal at two-loop level. Requiring the extra matter scale to be below the TeV scale, it is found that the addition of three vector-like fermion doublets with a mass around 700 GeV yields a perfect string-scale unification, provided that the affine levels are $(k_Y, k_2 ,k_3)=(13/3, 1, 2)$, as in the $SU(5) \times SU(5)$ string-GUT. Furthermore, if supersymmetry is broken at the unification scale, the Higgs mass is predicted in the range 125 GeV - 170 GeV, depending on the precise values of the top quark mass and $\tan \beta$ parameter.Comment: 11 pages, 4 eps figures, using jpconf style, talk given at CORFU2005, RTN meeting ``The Quest for Unification: Theory Confronts Experiment'', 11 - 18 September 2005, Corfu, Greec

Trans-translation is an appealing target for the development of new antimicrobial compounds

Because of the ever-increasing multidrug resistance in microorganisms, it is crucial that we find and develop new antibiotics, especially molecules with different targets and mechanisms of action than those of the antibiotics in use today. Translation is a fundamental process that uses a large portion of the cell’s energy, and the ribosome is already the target of more than half of the antibiotics in clinical use. However, this process is highly regulated, and its quality control machinery is actively studied as a possible target for new inhibitors. In bacteria, ribosomal stalling is a frequent event that jeopardizes bacterial wellness, and the most severe form occurs when ribosomes stall at the 30-end of mRNA molecules devoid of a stop codon. Trans-translation is the principal and most sophisticated quality control mechanism for solving this problem, which would otherwise result in inefficient or even toxic protein synthesis. It is based on the complex made by tmRNA and SmpB, and because trans-translation is absent in eukaryotes, but necessary for bacterial fitness or survival, it is an exciting and realistic target for new antibiotics. Here, we describe the current and future prospects for developing what we hope will be a novel generation of trans-translation inhibitors

Minimal Trinification

We study the trinified model, SU(3)_C x SU(3)_L x SU(3)_R x Z_3, with the minimal Higgs sector required for symmetry breaking. There are five Higgs doublets, and gauge-coupling unification results if all five are at the weak scale, without supersymmetry. The radiative see-saw mechanism yields sub-eV neutrino masses, without the need for intermediate scales, additional Higgs fields, or higher-dimensional operators. The proton lifetime is above the experimental limits, with the decay modes p -> \bar\nu K^+ and p -> \mu^+ K^0 potentially observable. We also consider supersymmetric versions of the model, with one or two Higgs doublets at the weak scale. The radiative see-saw mechanism fails with weak-scale supersymmetry due to the nonrenormalization of the superpotential, but operates in the split-SUSY scenario.Comment: 23 pages, uses axodra

Identification of phenotype-specific networks from paired gene expression-cell shape imaging data

The morphology of breast cancer cells is often used as an indicator of tumor severity and prognosis. Additionally, morphology can be used to identify more fine-grained, molecular developments within a cancer cell, such as transcriptomic changes and signaling pathway activity. Delineating the interface between morphology and signaling is important to understand the mechanical cues that a cell processes in order to undergo epithelial-to-mesenchymal transition and consequently metastasize. However, the exact regulatory systems that define these changes remain poorly characterized. In this study, we used a network-systems approach to integrate imaging data and RNA-seq expression data. Our workflow allowed the discovery of unbiased and context-specific gene expression signatures and cell signaling subnetworks relevant to the regulation of cell shape, rather than focusing on the identification of previously known, but not always representative, pathways. By constructing a cell-shape signaling network from shape-correlated gene expression modules and their upstream regulators, we found central roles for developmental pathways such as WNT and Notch, as well as evidence for the fine control of NF-kB signaling by numerous kinase and transcriptional regulators. Further analysis of our network implicates a gene expression module enriched in the RAP1 signaling pathway as a mediator between the sensing of mechanical stimuli and regulation of NF-kB activity, with specific relevance to cell shape in breast cancer

On Unification and Nucleon Decay in Supersymmetric Grand Unified Theories Based on SU(5)

We investigate the unification constraints in the minimal sypersymmetric grand unified theories based on SU(5) gauge symmetry. The most general constraints on the spectrum of minimal supersymmetric SU(5) and flipped SU(5) are shown. The upper bound on the mass of the colored Higgs mediating proton decay is discussed in detail in the context of the minimal supersymmetric SU(5). In the case of the minimal SUSY SU(5) we show that if we stick to the strongest bound on the colored triplet mass coming from dimension five proton decay contributions there is no hope to test this model at future nucleon decay experiments through the dimension six operators. We find a lower bound on the partial proton decay lifetime for all relevant channels in the context of flipped SUSY SU(5). We conclude that flipped SUSY SU(5) might be in trouble if proton decay is found at the next generation of experiments with a lifetime below 10^{37} years.Comment: 17 pages, 6 figures, some corrections and references adde

Visualizing Compaction of Polysomes in Bacteria.

International audienceDuring protein synthesis, many translating ribosomes are bound together with an mRNA molecule to form polysomes (or polyribosomes). While the spatial organization of bacterial polysomes has been well studied in vitro, little is known about how they cluster when cellular conditions are highly constrained. To better understand this, we used electron tomography, template matching, and three-dimensional modeling to analyze the supramolecular network of ribosomes after induction of translational pauses. In Escherichia coli, we overexpressed an mRNA carrying a polyproline motif known to induce pausing during translation. When working with a strain lacking transfer-messenger RNA, the principle actor in the "trans-translation" rescuing system, the cells survived the hijacking of the translation machinery but this resulted in a sharp modification of the ribosomal network. The results of our experiments demonstrate that single ribosomes are replaced with large amounts of compacted polysomes. These polysomes are highly organized, principally forming hairpins and dimers of hairpins that stack together. We propose that these spatial arrangements help maintain translation efficiency when the rescue systems are absent or overwhelmed

Testable Flipped SU(5) x U(1)_X Models

The little hierarchy between the GUT scale and the string scale may give us some hints that can be tested at the LHC. To achieve string-scale gauge coupling unification, we introduce additional vector-like particles. We require that these vector-like particles be standard, form complete GUT multiplets, and have masses around the TeV scale or close to the string scale. Interestingly, only the flipped SU(5) x U(1)_X models can work elegantly. We consider all possible sets of vector-like particles with masses around the TeV scale. And we introduce vector-like particles with masses close to the string scale which can mimic the string-scale threshold corrections. We emphasize that all of these vector-like particles can be obtained in the interesting flipped SU(5) x U(1)_X string models from the four-dimensional free fermionic string construction. Assuming the low-energy supersymmetry, high-scale supersymmetry, and split supersymmetry, we show that the string-scale gauge coupling unification can indeed be achieved in the flipped SU(5) x U(1)_X models. These models can be tested at the LHC by observing simple sets of vector-like particles at the TeV scale. Moreover, we discuss a simple flipped SU(5) x U(1)_X model with string-scale gauge coupling unification and high-scale supersymmetry by introducing only one pair of the vector-like particles at the TeV scale, and we predict the corresponding Higgs boson masses. Also, we briefly comment on the string-scale gauge coupling unification in the model with low-energy supersymmetry by introducing only one pair of the vector-like particles at the intermediate scale. And we briefly comment on the mixings among the SM fermions and the corresponding extra vector-like particles.Comment: RevTex4, 25 pages, 4 figures, 4 tables, comments and references added, version to appear in NP

Capsicumicine, a new bioinspired peptide from red peppers prevents staphylococcal biofilm in vitro and in vivo via a matrix anti-assembly mechanism of action

Staphylococci are pathogenic biofilm-forming bacteria and a source of multidrug resistance and/or tolerance causing a broad spectrum of infections. These bacteria are enclosed in a matrix that allows them to colonize medical devices, such as catheters and tissues, and that protects against antibiotics and immune systems. Advances in antibiofilm strategies for targeting this matrix are therefore extremely relevant. Here, we describe the development of the Capsicum pepper bioinspired peptide “capsicumicine.” By using microbiological, microscopic, and nuclear magnetic resonance (NMR) approaches, we demonstrate that capsicumicine strongly prevents methicillin-resistant Staphylococcus epidermidis biofilm via an extracellular “matrix anti-assembly” mechanism of action. The results were confirmed in vivo in a translational preclinical model that mimics medical device-related infection. Since capsicumicine is not cytotoxic, it is a promising candidate for complementary treatment of infectious diseases