Molecular Studies of T Cell Recognition and Cross-Reactivity: A Dissertation

Intracellular pathogens are recognized by a specialized subset of lymphocytes known as CD8+ T cells. Pathogen recognition by CD8+ T cells occurs through binding of T cell receptors (TCR) to processed antigens in complex with major histocompatibility complex (MHC) class I proteins. TCR engagement of antigens in complex with MHC class I typically lead to cytotoxic CD8+ T cell responses, which result in pathogen clearance. Due to the large number of foreign antigens that might be encountered by any given host a diverse repertoire of TCRs must be available for immune recognition. The main source of TCR diversity is generated by somatic recombination of the TCR genes. However, it has been suggested that selection eliminates so many recombined TCR sequences, that a high degree of TCR cross-reactivity must occur for the immune system to be able to recognize a large set of foreign pathogens. The work presented in this thesis was directed towards the understanding of the molecular mechanisms of CD8+ T cell recognition and cross-reactivity. Chapter I of this thesis gives an overview of the immune system, with a focus on CD8+ T cells. Chapter II of this thesis describes the development of novel bi-specific MHC heterodimers that are specific towards cross-reactive CD8+ T cells. Classically, MHC tetramers have been used for phenotypic characterization of antigen-specific T cells. However, identification of cross-reactive T cells requires the simultaneous use of two MHC tetramers, which was found to result in MHC tetramer cross-competition. For this reason, we generated bi-specific MHC heterodimers, which would not be affected by the affinity between the component peptide-MHC complexes for TCR. We generated T cell lines, which cross-react with antigens from lymphocytic choriomeningitis virus (LCMV) and vaccinia virus (VV), to test our bi-specific MHC heterodimers. We show that the heterobifunctional cross-linking utilized to generate bi-specific MHC heterodimers does not affect specific binding onto cross-reactive CD8+ T cells. Chapter III describes a mechanism for a cross-reactive CD8+ T cell response between the disparate antigens, lymphocytic choriomeningitis virus (LCMV)-GP34 (AVYNFATM) and vaccinia virus (VV)-A11R (AIVNYANL), which share the three underlined residues. The recognition determinants for LCMV-GP34 and VV-A11R were compared by an alanine/lysine scanning approach for both epitopes. Functional analysis of the mutated peptides clearly indicates that the shared P4N residue between LCMV-GP34 and VV-A11R is an important TCR contact for the recognition of both epitopes. In addition, we determined the crystal structures of both Kb-VV-A11R and Kb-LCMV-GP34. Structural analysis revealed that the two complexes are nearly identical structural mimics, which was unexpected due to the primary sequence disparity. Together with the functional studies, our results highlight that structural similarities between different peptide-MHC complexes can mediate cross-reactive T cell responses. Chapter IV of this thesis includes additional discussion, overall conclusions and future directions. Chapter V includes the protocols and the gene constructs that were used in this work. Also included in Chapter V are results from two unrelated incomplete projects which have yielded significant findings

Corrections to the thermodynamics of Schwarzschild-Tangherlini black hole and the generalized uncertainty principle

We investigate the thermodynamics of Schwarzschild-Tangherlini black hole in the context of the generalized uncertainty principle. The corrections to the Hawking temperature, entropy and the heat capacity are obtained via the modified Hamilton-Jacobi equation. These modifications show that the GUP changes the evolution of Schwarzschild-Tangherlini black hole. Specially, the GUP effect becomes susceptible when the radius or mass of black hole approach to the order of Planck scale, it stops radiating and leads to black hole remnant. Meanwhile, the Planck scale remnant can be confirmed through the analysis of the heat capacity. Those phenomenons imply that the GUP may give a way to solve the information paradox. Besides, we also investigate the possibilities to observe the black hole at LHC, the results demonstrate that the black hole can not be produced in the recent LHC.Comment: 12 pages, 6 figure

Stillbirth should be given greater priority on the global health agenda

Stillbirths are largely excluded from international measures of mortality and morbidity. Zeshan Qureshi and colleagues argue that stillbirth should be higher on the global health agenda

Measure representation and multifractal analysis of complete genomes

This paper introduces the notion of measure representation of DNA sequences. Spectral analysis and multifractal analysis are then performed on the measure representations of a large number of complete genomes. The main aim of this paper is to discuss the multifractal property of the measure representation and the classification of bacteria. From the measure representations and the values of the $D_{q}$ spectra and related $C_{q}$ curves, it is concluded that these complete genomes are not random sequences. In fact, spectral analyses performed indicate that these measure representations considered as time series, exhibit strong long-range correlation. For substrings with length K=8, the $D_{q}$ spectra of all organisms studied are multifractal-like and sufficiently smooth for the $C_{q}$ curves to be meaningful. The $C_{q}$ curves of all bacteria resemble a classical phase transition at a critical point. But the 'analogous' phase transitions of chromosomes of non-bacteria organisms are different. Apart from Chromosome 1 of {\it C. elegans}, they exhibit the shape of double-peaked specific heat function.Comment: 12 pages with 9 figures and 1 tabl

Selecting a single orientation for millimeter sized graphene sheets

We have used Low Energy Electron Microscopy (LEEM) and Photo Emission Electron Microscopy (PEEM) to study and improve the quality of graphene films grown on Ir(111) using chemical vapor deposition (CVD). CVD at elevated temperature already yields graphene sheets that are uniform and of monatomic thickness. Besides domains that are aligned with respect to the substrate, other rotational variants grow. Cyclic growth exploiting the faster growth and etch rates of the rotational variants, yields films that are 99 % composed of aligned domains. Precovering the substrate with a high density of graphene nuclei prior to CVD yields pure films of aligned domains extending over millimeters. Such films can be used to prepare cluster-graphene hybrid materials for catalysis or nanomagnetism and can potentially be combined with lift-off techniques to yield high-quality, graphene based electronic devices

Large Extra Dimension effects through Light-by-Light Scattering at the CERN LHC

Observing light-by-light scattering at the Large Hadron Collider (LHC) has received quite some attention and it is believed to be a clean and sensitive channel to possible new physics. In this paper, we study the diphoton production at the LHC via the process $\rm pp\rightarrow p\gamma\gamma p\rightarrow p\gamma\gamma p$ through graviton exchange in the Large Extra Dimension (LED) model. Typically, when we do the background analysis, we also study the Double Pomeron Exchange (DPE) of $\gamma\gamma$ production. We compare its production in the quark-quark collision mode to the gluon-gluon collision mode and find that contributions from the gluon-gluon collision mode are comparable to the quark-quark one. Our result shows, for extra dimension $\delta=4$, with an integrated luminosity $\rm {\cal L} = 200 fb^{-1}$ at the 14 TeV LHC, that diphoton production through graviton exchange can probe the LED effects up to the scale $\rm M_S=5.06 (4.51, 5.11) TeV$ for the forward detector acceptance $\xi_1 (\xi_2, \xi_3)$, respectively, where $0.0015<\xi_1<0.5$, $0.1<\xi_2<0.5$ and $0.0015<\xi_3<0.15$.Comment: 25 pages. 7 figs. Change some grammatical error

Sloshing of Cryogenic Helium Driven by Lateral Impulse/Gravity Gradient-Dominated/or g-Jitter-Dominated Accelerations and Orbital Dynamics

The coupling of slosh dynamics within a partially filled rotating dewar of superfluid helium 11 with spacecraft orbital dynamics is investigated in response to the environmental disturbances of (a) lateral impulses, (b) gravity gradients and (c) g-jitter forces. The purpose of this study is to investigate how the coupling of helium 11 fluid slosh dynamics driven by three cases of environmental force with spacecraft dynamics can affect the bubble deformations and their associated fluid and spacecraft mass centre fluctuations. The numerical computation of slosh dynamics is based on a rotational frame, while the spacecraft dynamics is associated with a non-rotational frame. Results show that the major contribution of orbital dynamics is driven by coupling with slosh dynamics. Neglecting the effect of slosh dynamics acting on the spacecraft may lead to the wrong results for the development of orbital and attitude control techniques

Optical and magnetic properties of Ni nanoparticles in rutile formed by Ni ion implantation

Crystalline Ni nanoparticles in the near surface of TiO2TiO2 (rutile) have been synthesized by Ni ion beam implantation at room temperature to a fluence of 1×1017/cm21×1017∕cm2. Transmission electron microscopy, optical absorption spectroscopy, and a superconducting quantum interference device magnetometer have been utilized to characterize the nanostructure, optical and magnetic properties of Ni particles in TiO2TiO2. Crystalline Ni nanoparticles with dimensions ranging 3–20 nm formed in the near surface of rutile, which caused a broad absorption band from 700 nm in the optical absorption spectrum. Magnetic measurement indicated that the coercive force of Ni nanoparticles was about 210 Oe at 10 K. The superparamagnetism of the nanoparticles was observed above blocking temperature T = 85 KT=85K.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/87774/2/043107_1.pd

In situ observation of stress relaxation in epitaxial graphene

Upon cooling, branched line defects develop in epitaxial graphene grown at high temperature on Pt(111) and Ir(111). Using atomically resolved scanning tunneling microscopy we demonstrate that these defects are wrinkles in the graphene layer, i.e. stripes of partially delaminated graphene. With low energy electron microscopy (LEEM) we investigate the wrinkling phenomenon in situ. Upon temperature cycling we observe hysteresis in the appearance and disappearance of the wrinkles. Simultaneously with wrinkle formation a change in bright field imaging intensity of adjacent areas and a shift in the moire spot positions for micro diffraction of such areas takes place. The stress relieved by wrinkle formation results from the mismatch in thermal expansion coefficients of graphene and the substrate. A simple one-dimensional model taking into account the energies related to strain, delamination and bending of graphene is in qualitative agreement with our observations.Comment: Supplementary information: S1: Photo electron emission microscopy and LEEM measurements of rotational domains, STM data of a delaminated bulge around a dislocation. S2: Movie with increasing brightness upon wrinkle formation as in figure 4. v2: Major revision including new experimental dat