B Cell Receptor Signalng in Germinal Centers

Germinal centers (GC) are sites of B cell clonal expansion, diversification, and antibody affinity selection. This process is limited and directed by T follicular helper cells that provide helper signals to B cells that endocytose, process, and present cognate antigens in proportion to receptor affinity. GCs play a crucial role in immunity by generating an evolving B cell pool that serves as the origin of protective memory B and plasma cells. Therefore, understanding how the GC reaction is controlled and how high-affinity clones are selected within the GC is fundamental to our understanding of adaptive immunity and of crucial importance to the development of vaccines. Under current models, GC selection is primarily determined by the antigen capture function of the B cell receptor (BCR). However, the BCR can also function as a signaling entity, and it is not well understood how signaling by the B cell receptor contributes to selection. The critical barriers to addressing this question have been a lack of specific BCR signaling reporters and models that do not compromise the initiation and maintenance of the GC reaction. In the first part of my thesis, I developed and characterized a “tracker” to detect active antigen engagement in vivo. Crucially, this tracker does not confer any cognate antigen for presentation, thus uncoupling the signaling and antigen capture functions of the BCR. In the second part of my thesis, I used this tracker in combination with a c-Myc reporter to investigate the role of BCR signaling in positive selection. I found that BCR signaling itself enhanced the ability of cells to receive T cell help, even when antigen presentation had been normalized. Transcriptome analysis showed that continuous BCR engagement was necessary for full induction of positive selection pathways and identified a subset of pre-memory B cells associated with lower magnitudes of positive selection. GC BCR engagement per se also induces metabolic changes that may prime cells to receive T cell help. To investigate the role of BCR selection in negative selection and survival, I developed a Bruton’s tyrosine kinase (BTK) drug-resistant mouse model. I found that continuous BCR engagement was necessary for the survival of light zone B cells and that survival was intrinsic to BCR signaling by inhibiting BTK. Lastly, I investigated the synergy between BCR signaling and T cell help in the presence of antigen targeting and low levels of drug treatment. Dampening of BCR signaling impacted the proliferation of cells after migration, despite normalized antigen presentation capacity. In summary, selection in the GC is dependent on both the signaling and endocytic functions of the BCR

The Role of Parvalbumin-positive Interneurons in Auditory Steady-State Response Deficits in Schizophrenia

© The Author(s) 2019. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.Despite an increasing body of evidence demonstrating subcellular alterations in parvalbumin-positive (PV+) interneurons in schizophrenia, their functional consequences remain elusive. Since PV+ interneurons are involved in the generation of fast cortical rhythms, these changes have been hypothesized to contribute to well-established alterations of beta and gamma range oscillations in patients suffering from schizophrenia. However, the precise role of these alterations and the role of different subtypes of PV+ interneurons is still unclear. Here we used a computational model of auditory steady-state response (ASSR) deficits in schizophrenia. We investigated the differential effects of decelerated synaptic dynamics, caused by subcellular alterations at two subtypes of PV+ interneurons: basket cells and chandelier cells. Our simulations suggest that subcellular alterations at basket cell synapses rather than chandelier cell synapses are the main contributor to these deficits. Particularly, basket cells might serve as target for innovative therapeutic interventions aiming at reversing the oscillatory deficits.Peer reviewe

The SKA Particle Array Prototype: The First Particle Detector at the Murchison Radio-astronomy Observatory

We report on the design, deployment, and first results from a scintillation detector deployed at the Murchison Radio-astronomy Observatory (MRO). The detector is a prototype for a larger array -- the Square Kilometre Array Particle Array (SKAPA) -- planned to allow the radio-detection of cosmic rays with the Murchison Widefield Array and the low-frequency component of the Square Kilometre Array. The prototype design has been driven by stringent limits on radio emissions at the MRO, and to ensure survivability in a desert environment. Using data taken from Nov.\ 2018 to Feb.\ 2019, we characterize the detector response while accounting for the effects of temperature fluctuations, and calibrate the sensitivity of the prototype detector to through-going muons. This verifies the feasibility of cosmic ray detection at the MRO. We then estimate the required parameters of a planned array of eight such detectors to be used to trigger radio observations by the Murchison Widefield Array.Comment: 17 pages, 14 figures, 3 table

Energetics and atomic mechanisms of dislocation nucleation in strained epitaxial layers

We study numerically the energetics and atomic mechanisms of misfit dislocation nucleation and stress relaxation in a two-dimensional atomistic model of strained epitaxial layers on a substrate with lattice misfit. Relaxation processes from coherent to incoherent states for different transition paths are studied using interatomic potentials of Lennard-Jones type and a systematic saddle point and transition path search method. The method is based on a combination of repulsive potential minimization and the Nudged Elastic Band method. For a final state with a single misfit dislocation, the minimum energy path and the corresponding activation barrier are obtained for different misfits and interatomic potentials. We find that the energy barrier decreases strongly with misfit. In contrast to continuous elastic theory, a strong tensile-compressive asymmetry is observed. This asymmetry can be understood as manifestation of asymmetry between repulsive and attractive branches of pair potential and it is found to depend sensitively on the form of the potential.Comment: 11 pages, 9 figures, to appear in Phys. Rev.

Initial low/hard state, multiple jet ejections and X-ray/radio correlations during the outburst of XTE J1859+226

We have studied the 1999 soft X-ray transient outburst of XTE J1859+226 at radio and X-ray wavelengths. The event was characterised by strong variability in the disc, corona and jet - in particular, a number of radio flares (ejections) took place and seemed well-correlated with hard X-ray events. Apparently unusual for the `canonical soft' X-ray transient, there was an initial period of low/hard state behaviour during the rise from quiescence but prior to the peak of the main outburst - we show that not only could this initial low/hard state be an ubiquitous feature of soft X-ray transient outbursts but that it could also be extremely important in our study of outburst mechanisms.Comment: 12 pages, Accepted for publication in MNRA

Dynamic Ordering and Transverse Depinning of a Driven Elastic String in a Disordered Media

We examine the dynamics of an elastic string interacting with quenched disorder driven perpendicular and parallel to the string. We show that the string is the most disordered at the depinning transition but with increasing drive partial ordering is regained. For low drives the noise power is high and we observe a 1/f^2 noise signature crossing over to a white noise character with low power at higher drives. For the parallel driven moving string there is a finite transverse critical depinning force with the depinning transition occuring by the formation of running kinks.Comment: 4 pages, 4 postscript figure

Renal safety of zoledronic acid with thalidomide in patients with myeloma: a pharmacokinetic and safety sub-study

BACKGROUND: Cases of impaired renal function have been reported in patients who had been treated with both zoledronic acid and thalidomide for myeloma. Hence, we conducted a safety study of zoledronic acid and thalidomide in myeloma patients participating in a trial of maintenance therapy. METHODS: Twenty-four patients who were enrolled in a large randomized trial of thalidomide vs no thalidomide maintenance therapy for myeloma, in which all patients also received zoledronic acid, were recruited to a pharmacokinetic and renal safety sub-study, and followed for up to 16 months. RESULTS: No significant differences by Wilcoxon rank-sum statistic were found in zoledronic acid pharmacokinetics or renal safety for up to 16 months in patients randomized to thalidomide or not. CONCLUSION: In myeloma patients receiving maintenance therapy, the combination of zoledronic acid and thalidomide appears to confer no additional renal safety risks over zoledronic acid alone

Nonequilibrium dislocation dynamics and instability of driven vortex lattices in two dimensions

We consider dislocations in a vortex lattice that is driven in a two-dimensional superconductor with random impurities. The structure and dynamics of dislocations is studied in this genuine nonequilibrium situation on the basis of a coarse-grained equation of motion for the displacement field. The presence of dislocations leads to a characteristic anisotropic distortion of the vortex density that is controlled by a Kardar-Parisi-Zhang nonlinearity in the coarse-grained equation of motion. This nonlinearity also implies a screening of the interaction between dislocations and thereby an instability of the vortex lattice to the proliferation of free dislocations.Comment: published version with minor correction

Unitarity of Little Higgs Models Signals New Physics of UV Completion

The ``Little Higgs'' opens up a new avenue for natural electroweak symmetry breaking in which the standard model Higgs particle is realized as a pseudo-Goldstone boson and thus is generically light. The symmetry breaking structure of the Little Higgs models predicts a large multiplet of (pseudo-)Goldstone bosons and their low energy interactions below the ultraviolet (UV) completion scale $\Lambda \sim 4\pi f \sim O(10)$ TeV, where $f$ is the Goldstone decay constant. We study unitarity of the Little Higgs models by systematically analyzing the high energy scatterings of these (pseudo-)Goldstone bosons. We reveal that the collective effect of the Goldstone scatterings via coupled channel analysis tends to push the unitarity violation scale $\Lambda_U$ significantly below the conventional UV scale $\Lambda \sim 4\pi f$ as estimated by naive dimensional analysis (NDA). Specifically, $\Lambda_U \sim (3-4)f$, lying in the multi-TeV range for $f\sim 1$ TeV. We interpret this as an encouraging sign that the upcoming LHC may explore aspects of Little Higgs UV completions, and we discuss some potential signatures. The meanings of the two estimated UV scales $\Lambda_U$ (from unitarity violation) and $\Lambda$ (from NDA) together with their implications for an effective field theory analysis of the Little Higgs models are also discussed.Comment: To match Phys.Lett.B version (9pp, only minor rewording

On two problems in graph Ramsey theory

We study two classical problems in graph Ramsey theory, that of determining the Ramsey number of bounded-degree graphs and that of estimating the induced Ramsey number for a graph with a given number of vertices. The Ramsey number r(H) of a graph H is the least positive integer N such that every two-coloring of the edges of the complete graph $K_N$ contains a monochromatic copy of H. A famous result of Chv\'atal, R\"{o}dl, Szemer\'edi and Trotter states that there exists a constant c(\Delta) such that r(H) \leq c(\Delta) n for every graph H with n vertices and maximum degree \Delta. The important open question is to determine the constant c(\Delta). The best results, both due to Graham, R\"{o}dl and Ruci\'nski, state that there are constants c and c' such that 2^{c' \Delta} \leq c(\Delta) \leq 2^{c \Delta \log^2 \Delta}. We improve this upper bound, showing that there is a constant c for which c(\Delta) \leq 2^{c \Delta \log \Delta}. The induced Ramsey number r_{ind}(H) of a graph H is the least positive integer N for which there exists a graph G on N vertices such that every two-coloring of the edges of G contains an induced monochromatic copy of H. Erd\H{o}s conjectured the existence of a constant c such that, for any graph H on n vertices, r_{ind}(H) \leq 2^{c n}. We move a step closer to proving this conjecture, showing that r_{ind} (H) \leq 2^{c n \log n}. This improves upon an earlier result of Kohayakawa, Pr\"{o}mel and R\"{o}dl by a factor of \log n in the exponent.Comment: 18 page