Conformational Changes Triggered by Mg2+ Mediate Transactivator Function

Transactivator protein C of bacteriophage mu is essential for the transition from middle to late gene expression during the phage life cycle. The unusual, multistep activation of mom promoter (Pmom) by C protein involves activator-mediated promoter unwinding to recruit RNA polymerase and subsequent enhanced promoter clearance of the enzyme. To achieve this, C binds its site overlapping the -35 region of the mom promoter with a very high affinity, in Mg2+-dependent fashion. Mg2+-mediated conformational transition in C is necessary for its DNA binding and transactivation. We have determined the residues in C which coordinate Mg2+, to induce allosteric transition in the protein, required for the specific interaction with DNA. Residues E26 and D40 in the putative metal binding motif (E26X10D37X2D40) present toward the N-terminus of the protein are found to be important for Mg2+ ion binding. Mutations in these residues lead to altered Mg2+-induced conformation, compromised DNA binding, and reduced levels of transcription activation. Although Mg2+ is widely used in various DNA transaction reactions, this report provides the first insights on the importance of the metal ion-induced allosteric transitions in regulating transcription factor function.

Efficient Output-Sensitive Construction of Reeb Graphs

The Reeb graph tracks topology changes in level sets of a scalar function and finds applications in scientific visualization and geometric modeling. This paper describes a near-optimal two-step algorithm that constructs the Reeb graph of a Morse function defined over manifolds in any dimension. The algorithm first identifies the critical points of the input manifold, and then connects these critical points in the second step to obtain the Reeb graph. A simplification mechanism based on topological persistence aids in the removal of noise and unimportant features. A radial layout scheme results in a feature-directed drawing of the Reeb graph. Experimental results demonstrate the efficiency of the Reeb graph construction in practice and its applications.

Gamma-ray luminosity function of gamma-ray bright AGNs

Detection of gamma-ray emissions from a class of active galactic nuclei (viz blazars), has been one of the important findings from the Compton Gamma-Ray Observatory (CGRO). However, their gamma-ray luminosity function has not-been well determined. Few attempts have been made in earlier works, where BL Lacs and Flat Spectrum Radio Quasars (FSRQs) have been considered as a single source class. In this paper, we investigated the evolution and gamma-ray luminosity function of FSRQs and BL Lacs separately. Our investigation indicates no evolution for BL Lacs, however FSRQs show significant evolution. Pure luminosity evolution is assumed for FSRQs and exponential and power law evolution models are examined. Due to the small number of sources, the low luminosity end index of the luminosity function for FSRQs is constrained with an upper limit. BL Lac luminosity function shows no signature of break. As a consistency check, the model source distributions derived from these luminosity functions show no significant departure from the observed source distributions.

Structural basis for the function of anti-idiotypic antibody in immune memory

We had earlier proposed a hypothesis to explain the mechanism of perpetuation of immunological memory based on the operation of idiotypic network in the complete absence of antigen. Experimental evidences were provided for memory maintenance through anti-idiotypic antibody (Ab2) carrying the internal image of the antigen. In the present work, we describe a structural basis for such memory perpetuation by molecular modeling and structural analysis studies. A three-dimensional model of Ab2 was generated and the structure of the antigenic site on the hemagglutinin protein H of Rinderpest virus was modeled using the structural template of hemagglutinin protein of Measles virus. Our results show that a large portion of heavy chain containing the CDR regions of Ab2 resembles the domain of the hemagglutinin housing the epitope regions. The similarity demonstrates that an internal image of the H antigen is formed in Ab2, which provides a structural basis for functional mimicry demonstrated earlier. This work brings out the importance of the structural similarity between a domain of hemagglutinin protein to that of its corresponding Ab2. It provides evidence that Ab2 is indeed capable of functioning as surrogate antigen and provides support to earlier proposed relay hypothesis which has provided a mechanism for the maintenance of immunological memory.

Melanopsin ganglion cell function in early age-related macular degeneration

Purpose Melanopsin-expressing retinal ganglion cells (mRGCs) have non-image forming functions including mediation of the pupil light reflex (PLR). There is limited knowledge about mRGC function in retinal disease. Initial retinal changes in age-related macular degeneration (AMD) occur in the paracentral region where mRGCs have their highest density, making them vulnerable during disease onset. In this cross-sectional clinical study, we measured the PLR to determine if mRGC function is altered in early stages of macular degeneration. Methods Pupil responses were measured in 8 early AMD patients (AREDS 2001 classification; mean age 72.6 ± 7.2 years, 5M, and 3F) and 12 healthy control participants (mean age 66.6 ± 6.1 years, 8M and 4F) using a custom-built Maxwellian-view pupillometer. Stimuli were 0.5 Hz sinewaves (10 s duration, 35.6° diameter) of short wavelength light (464nm, blue; retinal irradiance = 14.5 log quanta.cm-2.s-1) to produce high melanopsin excitation and of long wavelength light (638nm, red; retinal irradiance = 14.9 log quanta.cm-2.s-1), to bias activation to outer retina and provide a control. Baseline pupil diameter was determined during a 10 s pre-stimulus period. The post illumination pupil response (PIPR) was recorded for 40 s. The 6 s PIPR and maximum pupil constriction were expressed as percentage baseline (M ± SD). Results The blue PIPR was significantly less sustained (p<0.01) in the early AMD group (75.49 ± 7.88%) than the control group (58.28 ± 9.05%). The red PIPR was not significantly different (p>0.05) between the early AMD (84.79 ± 4.03%) and control groups (82.01 ± 5.86%). Maximum constriction amplitude in the early AMD group for blue (43.67 ± 6.35%) and red (48.64 ± 6.49%) stimuli were not significantly different to the control group for blue (39.94 ± 3.66%) and red (44.98 ± 3.15%) stimuli (p>0.05). Conclusions These results are suggestive of inner retinal mRGC deficits in early AMD. This non-invasive, objective measure of pupil responses may provide a new method for quantifying mRGC function and monitoring AMD progression.

Effect of curve crossing on absorption and resonance Raman spectra: analytical treatment for delta-function coupling in parabolic potentials

We propose an exactly solvable model for the two-state curve-crossing problem. Our model assumes the coupling to be a delta function. It is used to calculate the effect of curve crossing on the electronic absorption spectrum and the resonance Raman excitation profile.

Bounds on isoperimetric values of trees

Let G = (V, E) be a finite, simple and undirected graph. For S subset of V, let delta(S, G) = {(u, v) is an element of E : u is an element of S and v is an element of V - S} be the edge boundary of S. Given an integer i, 1 <= i <= vertical bar V vertical bar, let the edge isoperimetric value of G at i be defined as b(e)(i, G) = min(S subset of V:vertical bar S vertical bar=i)vertical bar delta(S, G)vertical bar. The edge isoperimetric peak of G is defined as b(e)(G) = max(1 <= j <=vertical bar V vertical bar)b(e)(j, G). Let b(v)(G) denote the vertex isoperimetric peak defined in a corresponding way. The problem of determining a lower bound for the vertex isoperimetric peak in complete t-ary trees was recently considered in [Y. Otachi, K. Yamazaki, A lower bound for the vertex boundary-width of complete k-ary trees, Discrete Mathematics, in press (doi: 10.1016/j.disc.2007.05.014)]. In this paper we provide bounds which improve those in the above cited paper. Our results can be generalized to arbitrary (rooted) trees. The depth d of a tree is the number of nodes on the longest path starting from the root and ending at a leaf. In this paper we show that for a complete binary tree of depth d (denoted as T-d(2)), c(1)d <= b(e) (T-d(2)) <= d and c(2)d <= b(v)(T-d(2)) <= d where c(1), c(2) are constants. For a complete t-ary tree of depth d (denoted as T-d(t)) and d >= c log t where c is a constant, we show that c(1)root td <= b(e)(T-d(t)) <= td and c(2)d/root t <= b(v) (T-d(t)) <= d where c(1), c(2) are constants. At the heart of our proof we have the following theorem which works for an arbitrary rooted tree and not just for a complete t-ary tree. Let T = (V, E, r) be a finite, connected and rooted tree - the root being the vertex r. Define a weight function w : V -> N where the weight w(u) of a vertex u is the number of its successors (including itself) and let the weight index eta(T) be defined as the number of distinct weights in the tree, i.e eta(T) vertical bar{w(u) : u is an element of V}vertical bar. For a positive integer k, let l(k) = vertical bar{i is an element of N : 1 <= i <= vertical bar V vertical bar, b(e)(i, G) <= k}vertical bar. We show that l(k) <= 2(2 eta+k k)

A new method for the in vivo identification of mechanical properties in arteries from cine MRI images: Theoretical framework and validation

Quantifying the stiffness properties of soft tissues is essential for the diagnosis of many cardiovascular diseases such as atherosclerosis. In these pathologies it is widely agreed that the arterial wall stiffness is an indicator of vulnerability. The present paper focuses on the carotid artery and proposes a new inversion methodology for deriving the stiffness properties of the wall from cine-MRI (magnetic resonance imaging) data. We address this problem by setting-up a cost function defined as the distance between the modeled pixel signals and the measured ones. Minimizing this cost function yields the unknown stiffness properties of both the arterial wall and the surrounding tissues. The sensitivity of the identified properties to various sources of uncertainty is studied. Validation of the method is performed on a rubber phantom. The elastic modulus identified using the developed methodology lies within a mean error of 9.6%. It is then applied to two young healthy subjects as a proof of practical feasibility, with identified values of 625 kPa and 587 kPa for one of the carotid of each subject.

Modeling strategies in longitudinal data analysis: Covariate, variance function and correlation structure selection

A modeling paradigm is proposed for covariate, variance and working correlation structure selection for longitudinal data analysis. Appropriate selection of covariates is pertinent to correct variance modeling and selecting the appropriate covariates and variance function is vital to correlation structure selection. This leads to a stepwise model selection procedure that deploys a combination of different model selection criteria. Although these criteria find a common theoretical root based on approximating the Kullback-Leibler distance, they are designed to address different aspects of model selection and have different merits and limitations. For example, the extended quasi-likelihood information criterion (EQIC) with a covariance penalty performs well for covariate selection even when the working variance function is misspecified, but EQIC contains little information on correlation structures. The proposed model selection strategies are outlined and a Monte Carlo assessment of their finite sample properties is reported. Two longitudinal studies are used for illustration.

Structural basis for the function of anti-idiotypic antibody in immune memory

We had earlier proposed a hypothesis to explain the mechanism of perpetuation of immunological memory based on the operation of idiotypic network in the complete absence of antigen. Experimental evidences were provided for memory maintenance through anti-idiotypic antibody (Ab(2)) carrying the internal image of the antigen. In the present work, we describe a structural basis for such memory perpetuation by molecular modeling and structural analysis studies. A three-dimensional model of Ab(2) was generated and the structure of the antigenic site on the hemagglutinin protein H of Rinderpest virus was modeled using the structural template of hemagglutinin protein of Measles virus. Our results show that a large portion of heavy chain containing the CDR regions of Ab(2) resembles the domain of the hemagglutinin housing the epitope regions. The similarity demonstrates that an internal image of the H antigen is formed in Ab(2), which provides a structural basis for functional mimicry demonstrated earlier. This work brings out the importance of the structural similarity between a domain of hemagglutinin protein to that of its corresponding Ab(2). It provides evidence that Ab(2) is indeed capable of functioning as surrogate antigen and provides support to earlier proposed relay hypothesis which has provided a mechanism for the maintenance of immunological memory.

Paraxial-wave optics and relativistic front description .1. The scalar theory

With the extension of the work of the preceding paper, the relativistic front form for Maxwell's equations for electromagnetism is developed and shown to be particularly suited to the description of paraxial waves. The generators of the Poincaré group in a form applicable directly to the electric and magnetic field vectors are derived. It is shown that the effect of a thin lens on a paraxial electromagnetic wave is given by a six-dimensional transformation matrix, constructed out of certain special generators of the Poincaré group. The method of construction guarantees that the free propagation of such waves as well as their transmission through ideal optical systems can be described in terms of the metaplectic group, exactly as found for scalar waves by Bacry and Cadilhac. An alternative formulation in terms of a vector potential is also constructed. It is chosen in a gauge suggested by the front form and by the requirement that the lens transformation matrix act locally in space. Pencils of light with accompanying polarization are defined for statistical states in terms of the two-point correlation function of the vector potential. Their propagation and transmission through lenses are briefly considered in the paraxial limit. This paper extends Fourier optics and completes it by formulating it for the Maxwell field. We stress that the derivations depend explicitly on the "henochromatic" idealization as well as the identification of the ideal lens with a quadratic phase shift and are heuristic to this extent.