Spatial arrangement of LD motif-interacting residues on focal adhesion targeting domain of Focal Adhesion Kinase determine domain-motif interaction affinity and specificity

Background: Leucine rich Aspartate motifs (LD motifs) are molecular recognition motifs on Paxillin that recognize LD-motif binding domains (LDBD) of a number of focal adhesion proteins in order to carry out downstream signaling and actin cytoskeleton remodeling. In this study, we identified structural features within LDBDs that influence their binding affinity with Paxillin LD motifs. Methods: Various point mutants of focal adhesion targeting (FAT) domain of Focal Adhesion Kinase (FAK) were created by moving a key Lysine residue two and three helical turns in order to match the unique conformations as observed in LDBDs of two other focal adhesion proteins, Vinculin and CCM3. Results: This led to identify a mutant of FAT domain of FAK, named as FAT(NV) (Asn992 of FAT domain was replaced by Val), with remarkable high affinity for LD1 (Kd = 1.5 µM vs no-binding with wild type) and LD2 peptides (Kd = 7.2 µM vs 63 µM with wild type). Consistently, the focal adhesions of MCF7 cells expressing FAK(NV) were highly stable (turnover rate = 1.25 × 10-5 µm2/s) as compared to wild type FAK transfected cells (turnover rate = 1.5 × 10-3 µm2/s). Conclusions: We observed that the relative disposition of key LD binding amino-acids at LDBD surface, hydrophobic burial of long Leucine side chains of LD-motifs and complementarity of charged surfaces are the key factors determining the binding affinities of LD motifs with LDBDs. General significance: Our study will help in protein engineering of FAT domain of FAK by modulating FAK-LD motif interactions which have implications in cellular focal adhesions and cell migration

c=1 Matrix Models: Equivalences and Open-Closed String Duality

We give an explicit demonstration of the equivalence between the Normal Matrix Model (NMM) of c=1 string theory at selfdual radius and the Kontsevich-Penner (KP) model for the same string theory. We relate macroscopic loop expectation values in the NMM to condensates of the closed string tachyon, and discuss the implications for open-closed duality. As in c<1, the Kontsevich-Miwa transform between the parameters of the two theories appears to encode open-closed string duality, though our results also exhibit some interesting differences with the c<1 case. We also briefly comment on two different ways in which the Kontsevich model originates.Comment: 27 pages, latex, 1 figure, typos, discussion added, acknowledgements update

Exclusive Queueing Process with Discrete Time

In a recent study [C Arita, Phys. Rev. E 80, 051119 (2009)], an extension of the M/M/1 queueing process with the excluded-volume effect as in the totally asymmetric simple exclusion process (TASEP) was introduced. In this paper, we consider its discrete-time version. The update scheme we take is the parallel one. A stationary-state solution is obtained in a slightly arranged matrix product form of the discrete-time open TASEP with the parallel update. We find the phase diagram for the existence of the stationary state. The critical line which separates the parameter space into the regions with and without the stationary state can be written in terms of the stationary current of the open TASEP. We calculate the average length of the system and the average number of particles

Open/closed duality for FZZT branes in c=1

We describe how the matrix integral of Imbimbo and Mukhi arises from a limit of the FZZT partition function in the double-scaled c=1 matrix model. We show a similar result for 0A and comment on subtleties in 0B.Comment: 26 pages, 2 figure

New physics, the cosmic ray spectrum knee, and pppp cross section measurements

We explore the possibility that a new physics interaction can provide an explanation for the knee just above $10^6$ GeV in the cosmic ray spectrum. We model the new physics modifications to the total proton-proton cross section with an incoherent term that allows for missing energy above the scale of new physics. We add the constraint that the new physics must also be consistent with published $pp$ cross section measurements, using cosmic ray observations, an order of magnitude and more above the knee. We find that the rise in cross section required at energies above the knee is radical. The increase in cross section suggests that it may be more appropriate to treat the scattering process in the black disc limit at such high energies. In this case there may be no clean separation between the standard model and new physics contributions to the total cross section. We model the missing energy in this limit and find a good fit to the Tibet III cosmic ray flux data. We comment on testing the new physics proposal for the cosmic ray knee at the Large Hadron Collider.Comment: 17 pages, 4 figure

Alterations to nuclear architecture and genome behavior in senescent cells.

The organization of the genome within interphase nuclei, and how it interacts with nuclear structures is important for the regulation of nuclear functions. Many of the studies researching the importance of genome organization and nuclear structure are performed in young, proliferating, and often transformed cells. These studies do not reveal anything about the nucleus or genome in nonproliferating cells, which may be relevant for the regulation of both proliferation and replicative senescence. Here, we provide an overview of what is known about the genome and nuclear structure in senescent cells. We review the evidence that nuclear structures, such as the nuclear lamina, nucleoli, the nuclear matrix, nuclear bodies (such as promyelocytic leukemia bodies), and nuclear morphology all become altered within growth-arrested or senescent cells. Specific alterations to the genome in senescent cells, as compared to young proliferating cells, are described, including aneuploidy, chromatin modifications, chromosome positioning, relocation of heterochromatin, and changes to telomeres

Synthesis of accelerograms compatible with the Chinese GB 50011-2001 design spectrum via harmonic wavelets: artificial and historic records

A versatile approach is employed to generate artificial accelerograms which satisfy the compatibility criteria prescribed by the Chinese aseismic code provisions GB 50011-2001. In particular, a frequency dependent peak factor derived by means of appropriate Monte Carlo analyses is introduced to relate the GB 50011-2001 design spectrum to a parametrically defined evolutionary power spectrum (EPS). Special attention is given to the definition of the frequency content of the EPS in order to accommodate the mathematical form of the aforementioned design spectrum. Further, a one-to-one relationship is established between the parameter controlling the time-varying intensity of the EPS and the effective strong ground motion duration. Subsequently, an efficient auto-regressive moving-average (ARMA) filtering technique is utilized to generate ensembles of non-stationary artificial accelerograms whose average response spectrum is in a close agreement with the considered design spectrum. Furthermore, a harmonic wavelet based iterative scheme is adopted to modify these artificial signals so that a close matching of the signals’ response spectra with the GB 50011-2001 design spectrum is achieved on an individual basis. This is also done for field recorded accelerograms pertaining to the May, 2008 Wenchuan seismic event. In the process, zero-phase high-pass filtering is performed to accomplish proper baseline correction of the acquired spectrum compatible artificial and field accelerograms. Numerical results are given in a tabulated format to expedite their use in practice

Uncovering precision phenotype-biomarker associations in traumatic brain injury using topological data analysis

Background: Traumatic brain injury (TBI) is a complex disorder that is traditionally stratified based on clinical signs and symptoms. Recent imaging and molecular biomarker innovations provide unprecedented opportunities for improved TBI precision medicine, incorporating patho-anatomical and molecular mechanisms. Complete integration of these diverse data for TBI diagnosis and patient stratification remains an unmet challenge. Methods and findings: The Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) Pilot multicenter study enrolled 586 acute TBI patients and collected diverse common data elements (TBI-CDEs) across the study population, including imaging, genetics, and clinical outcomes. We then applied topology-based data-driven discovery to identify natural subgroups of patients, based on the TBI-CDEs collected. Our hypothesis was two-fold: 1) A machine learning tool known as topological data analysis (TDA) would reveal data-driven patterns in patient outcomes to identify candidate biomarkers of recovery, and 2) TDA-identified biomarkers would significantly predict patient outcome recovery after TBI using more traditional methods of univariate statistical tests. TDA algorithms organized and mapped the data of TBI patients in multidimensional space, identifying a subset of mild TBI patients with a specific multivariate phenotype associated with unfavorable outcome at 3 and 6 months after injury. Further analyses revealed that this patient subset had high rates of post-traumatic stress disorder (PTSD), and enrichment in several distinct genetic polymorphisms associated with cellular responses to stress and DNA damage (PARP1), and in striatal dopamine processing (ANKK1, COMT, DRD2). Conclusions: TDA identified a unique diagnostic subgroup of patients with unfavorable outcome after mild TBI that were significantly predicted by the presence of specific genetic polymorphisms. Machine learning methods such as TDA may provide a robust method for patient stratification and treatment planning targeting identified biomarkers in future clinical trials in TBI patients

Relativistic Three-Dimensional Two- and Three-Body Equations on a Null Plane and Applications to Meson and Baryon Regge Trtajectories

We start from a field-theoretical model of zero range approximation to derive three-dimensional relativistic two- and three-body equations on a null plane. We generalize those equations to finite range interactions. We propose a three-body null-plane equation whose form is different from the one presented earlier in the framework of light-cone dynamics. We discuss the choices of the kernels in two- and three-body cases and apply our model to the description of meson and baryon Regge trajectories. Our approach overcomes some theoretical and phenomenological difficulties met in preceding relativized treatments of the three-body problem.Comment: 35 pages LaTex, 6 figs (available from [email protected]