First passage time of N excluded volume particles on a line

Motivated by recent single molecule studies of proteins sliding on a DNA molecule, we explore the targeting dynamics of N particles ("proteins") sliding diffusively along a line ("DNA") in search of their target site (specific target sequence). At lower particle densities, one observes an expected reduction of the mean first passage time proportional to 1/N**2, with corrections at higher concentrations. We explicitly take adsorption and desorption effects, to and from the DNA, into account. For this general case, we also consider finite size effects, when the continuum approximation based on the number density of particles, breaks down. Moreover, we address the first passage time problem of a tagged particle diffusing among other particles.Comment: 9 pages, REVTeX, 6 eps figure

Transport and energy in India. Energy used by Indian transport systems and consequent emissions: the need for quantitative analyses (Well-to-Wheel, Lifecycle)

The purpose of this work is, at first, a general overview on the state-of-art of the transportation system in India outlining the related energy consumption, for the different transport modes, with consequent estimated emissions. These elements are essential for the preparation of a high-level strategic transport planning on the whole energy issue, to help India in the choices of most suitable transportation systems, according to the well-to-wheel analysis (WTW). Pursuing a WTW global index for India that takes into account both the energy and environmental aspects on a uniform basis is an important aim: it allows the best choices to be made as well as enabling the comparison between some of the most important powertrain and fuel options on the Indian market, the results are discussed from three different points of view: energy, environmental and economic impact

Inhibition of AKT with the Orally Active Allosteric AKT Inhibitor, MK-2206, Sensitizes Endometrial Cancer Cells to Progestin

Progestin resistance is a major obstacle to treating early stage, well-differentiated endometrial cancer as well as recurrent endometrial cancer. The mechanism behind the suboptimal response to progestin is not well understood. The PTEN tumor suppressor gene is frequently mutated in type I endometrial cancers and this mutation results in hyperactivation of the PI3K/AKT pathway. We hypothesized that increased activation of AKT promotes an inadequate response to progestins in endometrial cancer cells. Ishikawa cells stably transfected with progesterone receptor B (PRB23 cells) were treated with the AKT inhibitor, MK-2206, which effectively decreased levels of p(Ser473)-AKT in a dose-dependent (10 nM to 1 uM) and time-dependent manner (0.5 h to 24 h). MK-2206 inhibited levels of p(Thr308)-AKT and a downstream target, p(Thr246)-PRAS40, but did not change levels of p(Thr202/Tyr204)ERK or p(Thr13/Tyr185)SAPK/JNK, demonstrating specificity of MK-2206 for AKT. Additionally, MK-2206 treatment of PRB23 cells resulted in a significant increase in levels of progesterone receptor B (PRB) protein. Microarray analysis of PRB23 cells identified PDK4 as the most highly upregulated gene among 70 upregulated genes in response to R5020. Inhibition of AKT further upregulated progestin-mediated expression of PDK4 but did not affect another progestin-responsive gene, SGK1. Treatment of PRB23 cells with R5020 and MK-2206 independently decreased viability of cells while the combination of R5020 and MK-2206 caused the greatest decrease in cell viability. Furthermore, mice with xenografted tumors treated with MK-2206 alone or with progesterone alone exhibited modest reductions in their tumor volume. The largest decrease in tumor size was observed in the mice treated with both MK-2206 and progesterone; these tumors exhibited the least proliferation (Ki67) and the most apoptosis (cleaved caspase-3) of all the treatment groups. In summary, inhibition of AKT stabilizes the Progesterone Receptor B and augments progesterone response in endometrial cancer cells that have hyperactivated AKT

Advanced 3D modeling versus Building Information Modeling: the case study of Palazzo Ettoreo in Sacile (Italy)

This paper presents an experience of 3D modeling starting from laser scanning data and following two alternative approaches: the first one, called \u201cAdvanced 3D modeling\u201d, based on an original meshing algorithm, while the second make use of Revit BIM software. The case study in Palace Ettoreo in Sacile (Pordenone, Italy), constructed in Renaissance Venetian style in the 16th century: it has a trapezoid plan and is developed on three floors, with the ground one endowing a portico on two fa\ue7ades. The palace has been surveyed by two terrestrial laser scanners: a Riegl Z420i for 5 external scans and a FARO Photon 120 for 53 internal scans; also a topographic surveying of 270 targets have been carried out. The final TLS cloud has 1,4 billions of points. The Advanced 3D modeling has produced a \u201csmart\u201d mesh, allowing also to model the elements with deformations (out of plumb, bulges and troughs). Moreover, this model drastically reduce the stored data: the whole palace is modeled by 111.496 polygons only. The modeling with Revit follows the classical flowchart where the principal architectonical elements are gradually composed: this HBIM process has required a strong manual work in exploiting the available parametric objects and/or in the definition of new objects. Comparing the two models with respect the points cloud, both have evidenced advantages and limitations: therefore, the best solution is a process involving their combination. At the beginning, the Advanced 3D modeling is performed onto the points cloud, so well exploiting the segmentation tools and the smart meshing of the surfaces preserving any geometrical irregularity. Such obtained model allows metrical and morphological evaluation on the various structural and architectonical elements. Afterwards, this very light model becomes the entry data for the modeling in BIM environment, where also the shape of irregular elements are so imported

Molecular composition of organic aerosols at urban background and road tunnel sites using ultra-high resolution mass spectrometry

Organic aerosol composition in the urban atmosphere is highly complex and strongly influenced by vehicular emissions which vary according to the make-up of the vehicle fleet. Normalized test measurements do not necessarily reflect real-world emission profiles and road tunnels are therefore ideal locations to characterise realistic traffic particle emissions with minimal interference from other particle sources and from atmospheric aging processes affecting their composition. In the current study, the composition of fine particles (diameter ≤2.5 μm) at an urban background site (Elms Road Observatory Site) and a road tunnel (Queensway) in Birmingham, UK, were analysed with direct infusion, nano-electrospray ionisation ultrahigh resolution mass spectrometry (UHRMS). The overall particle composition at these two sites is compared with an industrial harbour site in Cork, Ireland, with special emphasis on oxidised mono-aromatics, polycyclic aromatic hydrocarbons (PAHs) and nitro-aromatics. Different classification criteria, such as double bond equivalents, aromaticity index and aromaticity equivalent are used and compared to assess the fraction of aromatic components in the approximately one thousand oxidized organic compounds at the different sampling locations.University of Birmingham, European Research Council (Grant ID: 279405

Kinetics and thermodynamics of salt-dependent T7 gene 2.5 protein binding to single- and double-stranded DNA

Bacteriophage T7 gene 2.5 protein (gp2.5) is a single-stranded DNA (ssDNA)-binding protein that has essential roles in DNA replication, recombination and repair. However, it differs from other ssDNA-binding proteins by its weaker binding to ssDNA and lack of cooperative ssDNA binding. By studying the rate-dependent DNA melting force in the presence of gp2.5 and its deletion mutant lacking 26 C-terminal residues, we probe the kinetics and thermodynamics of gp2.5 binding to ssDNA and double-stranded DNA (dsDNA). These force measurements allow us to determine the binding rate of both proteins to ssDNA, as well as their equilibrium association constants to dsDNA. The salt dependence of dsDNA binding parallels that of ssDNA binding. We attribute the four orders of magnitude salt-independent differences between ssDNA and dsDNA binding to nonelectrostatic interactions involved only in ssDNA binding, in contrast to T4 gene 32 protein, which achieves preferential ssDNA binding primarily through cooperative interactions. The results support a model in which dimerization interactions must be broken for DNA binding, and gp2.5 monomers search dsDNA by 1D diffusion to bind ssDNA. We also quantitatively compare the salt-dependent ssDNA- and dsDNA-binding properties of the T4 and T7 ssDNA-binding proteins for the first time

Arbitrary Choice of Basic Variables in Density Functional Theory. II. Illustrative Applications

Our recent theory (Ref. 1) enables us to choose arbitrary quantities as the basic variables of the density functional theory. In this paper we apply it to several cases. In the case where the occupation matrix of localized orbitals is chosen as a basic variable, we can obtain the single-particle equation which is equivalent to that of the LDA+U method. The theory also leads to the Hartree-Fock-Kohn-Sham equation by letting the exchange energy be a basic variable. Furthermore, if the quantity associated with the density of states near the Fermi level is chosen as a basic variable, the resulting single-particle equation includes the additional potential which could mainly modify the energy-band structures near the Fermi level.Comment: 27 page

Oncogenic Ras Disrupts Epithelial Integrity by Activating the Transmembrane Serine Protease Hepsin

Ras proteins play a causal role in human cancer by activating multiple pathways that promote cancer growth and invasion. However, little is known about how Ras induces the first diagnostic features of invasion in solid tumors, including loss of epithelial integrity and breaching of the basement membrane (BM). In this study, we found that oncogenic Ras strongly promotes the activation of hepsin, a member of the hepsin/TMPRSS type II transmembrane serine protease family. Mechanistically, the Ras-dependent hepsin activation was mediated via Raf-MEK-ERK signaling, which controlled hepsin protein stability through the heat shock transcription factor-1 stress pathway. In Ras-transformed three-dimensional mammary epithelial culture, ablation of hepsin restored desmosomal cell-cell junctions, hemidesmosomes, and BM integrity and epithelial cohesion. In tumor xenografts harboring mutant KRas, silencing of hepsin increased local invasion concomitantly with accumulation of collagen IV. These findings suggest that hepsin is a critical protease for Ras-dependent tumorigenesis, executing cell-cell and cell-matrix pathologies important for early tumor dissemination. Significance: These findings identify the cell-surface serine protease hepsin as a potential therapeutic target for its role in oncogenic Ras-mediated deregulation of epithelial cell-cell and cell-matrix interactions and cohesion of epithelial structure.Peer reviewe

Integrated positron emission tomography/computed tomography fusion imaging: An emerging gold standard in lung cancer

Positron emission tomography (PET) has emerged as an important diagnostic tool in the management of lung cancers. Although PET is sensitive in detection of lung cancer, but FDG (2-deoxy-2- 18 fluro-D-glucose) is not tumor specific and may accumulate in a variety of nonmalignant conditions occasionally giving false positive result. Addition of CT to PET improves specificity foremost, but also sensitivity in tumor imaging. Thus, PET/CT fusion images are a more accurate test than either of its individual components and are probably also better than side-by-side viewing of images from both modalities. PET/CT fusion images are useful in differentiating between malignant and benign disease, fibrosis and recurrence, staging and in changing patient management to more appropriate therapy. With analysis and discussion it appears that PET/ CT fusion images have the potential to dramatically improve our ability to manage the patients with lung cancer and is contributing to our understanding of cancer cell biology and in development of new therapies

Coherent coupling between radio frequency, optical, and acoustic waves in piezo-optomechanical circuits

The interaction of optical and mechanical modes in nanoscale optomechanical systems has been widely studied for applications ranging from sensing to quantum information science. Here, we develop a platform for cavity optomechanical circuits in which localized and interacting 1550 nm photons and 2.4 GHz phonons are combined with photonic and phononic waveguides. Working in GaAs facilitates manipulation of the localized mechanical mode either with a radio frequency field through the piezo-electric effect, or optically through the strong photoelastic effect. We use this to demonstrate a novel acoustic wave interference effect, analogous to coherent population trapping in atomic systems, in which the coherent mechanical motion induced by the electrical drive can be completely cancelled out by the optically-driven motion. The ability to manipulate cavity optomechanical systems with equal facility through either photonic or phononic channels enables new device and system architectures for signal transduction between the optical, electrical, and mechanical domains