On the Regulation of T Cell­‐dependent Immune Responses

The immune system responds to an enormous variety of pathogens as well as to malignant cells. Since healthy tissues may also be damaged during immune responses, multiple mechanisms have evolved to shape and limit immune responses, in order to protect the integrity of the respective tissue. Understanding the basic mechanisms of immune regulation will help to successfully reprogram immune reactivity in immune-mediated diseases. T cell responses can be regulated by multiple factors including intrinsic and extrinsic modulators. In the first part of this thesis we aimed to understand how the Nck adaptor proteins, as intrinsic modulators, control T cell effector function. Nck adaptor proteins stabilize proximal signaling complexes of T cell receptors (TCR) in the cytoplasm, thereby enhancing TCR signaling. We found that T cell-specific deletion of Nck proteins (Nck.T-/-) lead to impaired germinal center formation, which is the central event for productive T cell-dependent antibody production. The number of follicular helper T (Tfh) cells, which are essential for germinal center formation, was decreased in the spleen of Nck.T-/- mice in comparison to wild type controls. The production of cytokines, such as IL-4, IL-10, and IL-21, by Tfh cells was reduced. The dysfunction of Tfh cells was associated with decreased Akt phosphorylation and intensified apoptosis of Tfh cells. Consequently, T cell-dependent antibody responses were reduced in regard to quantity as well as quality by affinity maturation. Furthermore, using experimental autoimmune encephalomyelitis as an autoimmune model lower disease scores, delayed dynamics and faster recovery were observed in Nck.T-/- mice in comparison to wild type animals. Together, our findings show an essential role for the Nck adapter proteins in the generation of potent effector T cells. Thus, defects in Nck protein function may have a so far un-recognized role in human diseases with defective T cell responses. The second part focused on the role of the secreted protein Dickkopf-3 (DKK3) in modulating T cell responses against transplanted tumors. Mesenchymal stem cells (MSCs) are known to limit T cell responses in vivo. We found that DKK3 is produced by MSCs and contributed to MSC-mediated immune-suppression. Wild type MSCs inhibited anti-tumor responses whereas DKK3 deficient MSCs did not affect the rejection process. Impaired chemokine production by DKK3-/- MSCs could be related to enhanced infiltration of CD8+ T cells within the DKK3-/- MSC-inoculated tumors. In addition, loss of DKK3 in MSCs resulted in increased expression of MHC class II antigens that may render MSCs more immunogenic rather than immune-suppressive. The higher expression of MHC II in DKK3-/- MSCs was associated with decreased mTOR activity and thereby enhanced autophagy. We hypothesize that DKK3 may act as a positive modulator of the non-canonical Wnt/PCP pathway. Presently, DKK3 is being suggested as a potential anti-tumoral agent in human cancers based on reports that DKK3 is a tumor-suppressor. Our studies showing an immune-suppressive effect of DKK3 in the tumor mass may counteract these optimistic expectations and call for further detailed studies on the role of DKK3 in tumor development and in the respective immune responses before starting clinical trials. Together, our studies contribute to a better understanding of mechanisms, which are involved in the control of T cell responses, and open new perspectives for further investigations

Computational Aspects of Optional P\'{o}lya Tree

Optional P\'{o}lya Tree (OPT) is a flexible non-parametric Bayesian model for density estimation. Despite its merits, the computation for OPT inference is challenging. In this paper we present time complexity analysis for OPT inference and propose two algorithmic improvements. The first improvement, named Limited-Lookahead Optional P\'{o}lya Tree (LL-OPT), aims at greatly accelerate the computation for OPT inference. The second improvement modifies the output of OPT or LL-OPT and produces a continuous piecewise linear density estimate. We demonstrate the performance of these two improvements using simulations

Tris(piperazinediium) phosphatododeca­molybo(V,VI)phosphate

The title compound, (C4H12N2)3[PMo12O40] or (H2pip)3[PMo12O40] (pip is piperazine), was prepared under hydro­thermal conditions. The asymmetric unit contains one-sixth of a mixed-valent Mo(V,VI) pseudo-Keggin-type [PMo12O40]6− anion and half a piperazinediium cation, (H2pip)2+. The discrete Keggin-type [PMo12O40]6- anion has site symmetry and the three (H2pip)2+ cations each have site symmetry at the centres of the mol­ecules. The central P atom is on special position , which is a roto-inversion position and generates the disorder of the PO4 tetra­hedron. Furthermore, six doubly bridging oxide groups are also disordered with an occupancy factor of 0.5 for each O atom. The anions and cations are linked by an extensive network of inter­molecular N—H⋯O and C—H⋯O hydrogen bonds

Bis[N,N-bis­(1-allyl-1H-benzimidazol-2-ylmethyl-κN 3)benzyl­amine-κN]cadmium dipicrate

The crystal structure of the title compound, [Cd(C29H29N5)2](C6H2N3O7)2, consists of CdII complex cations and picrate anions. In the complex cation, the CdII ion is chelated by two bis­(1-allyl­benzimidazol-2-ylmeth­yl)benzyl­amine (babb) ligands in a distorted octa­hedral geometry. Extensive C—H⋯O hydrogen bonding occurs between cations and anions in the crystal structure

Optical and Gamma-Ray Variability Behaviors of 3C 454.3 from 2006 to 2011

We present our photometric monitoring of a flat spectrum radio quasar (FSRQ) 3C 454.3 at Yunnan observatories from 2006 to 2011. We find that the optical color of 3C 454.3 shows obvious redder-when-brighter trend, which reaches a saturation stage when the source is brighter than 15.15 mag at V band. We perform a simulation with multiple values of disk luminosity and spectral index to reproduce the magnitude-color diagram. The results show that the contamination caused by the disk radiation alone is difficult to produce the observed color variability. The variability properties during the outburst in December 2009 are also compared with $\gamma$-ray data derived from Fermi $\gamma$-ray space telescope. The flux variation of these two bands follow a linear relation with $F_{\gamma} \propto F_R^{1.14\pm0.07}$, which provides an observational evidence for external Compton process in 3C 454.3. Meanwhile, this flux correlation indicates that electron injection is the main mechanism for variability origin. We also explore the variation of the flux ratio $F_{\gamma}/F_R$ and the detailed structures in the lightcurves, and discuss some possible origins for the detailed variability behaviors.Comment: accepted for publication in The Astrophysical Journal, 5 figures, 2 table

TWIN: TWo-stage Interest Network for Lifelong User Behavior Modeling in CTR Prediction at Kuaishou

Life-long user behavior modeling, i.e., extracting a user's hidden interests from rich historical behaviors in months or even years, plays a central role in modern CTR prediction systems. Conventional algorithms mostly follow two cascading stages: a simple General Search Unit (GSU) for fast and coarse search over tens of thousands of long-term behaviors and an Exact Search Unit (ESU) for effective Target Attention (TA) over the small number of finalists from GSU. Although efficient, existing algorithms mostly suffer from a crucial limitation: the \textit{inconsistent} target-behavior relevance metrics between GSU and ESU. As a result, their GSU usually misses highly relevant behaviors but retrieves ones considered irrelevant by ESU. In such case, the TA in ESU, no matter how attention is allocated, mostly deviates from the real user interests and thus degrades the overall CTR prediction accuracy. To address such inconsistency, we propose \textbf{TWo-stage Interest Network (TWIN)}, where our Consistency-Preserved GSU (CP-GSU) adopts the identical target-behavior relevance metric as the TA in ESU, making the two stages twins. Specifically, to break TA's computational bottleneck and extend it from ESU to GSU, or namely from behavior length $10^2$ to length $10^4-10^5$, we build a novel attention mechanism by behavior feature splitting. For the video inherent features of a behavior, we calculate their linear projection by efficient pre-computing \& caching strategies. And for the user-item cross features, we compress each into a one-dimentional bias term in the attention score calculation to save the computational cost. The consistency between two stages, together with the effective TA-based relevance metric in CP-GSU, contributes to significant performance gain in CTR prediction.Comment: Accepted by KDD 202

VASP Activation via the Gα13/RhoA/PKA Pathway Mediates Cucurbitacin-B-Induced Actin Aggregation and Cofilin-Actin Rod Formation

Cucurbitacin B (CuB), a potent antineoplastic agent of cucurbitacin triterpenoids, induces rapid disruption of actin cytoskeleton and aberrant cell cycle inhibiting carcinogenesis. However, the underlying molecular mechanism of such anticancer effects remains incompletely understood. In this study, we showed that CuB treatment rapidly induced vasodilator-stimulated phosphoprotein (VASP) phosphorylation (i.e. activation) at the Ser157 residue and generated VASP clumps which were co-localized with amorphous actin aggregates prior to the formation of highly-ordered cofilin-actin rods in melanoma cells. Knockdown of VASP or inhibition of VASP activation using PKA-specific inhibitor H89 suppressed CuB-induced VASP activation, actin aggregation and cofilin-actin rod formation. The VASP activation was mediated by cAMP-independent PKA activation as CuB decreased the levels of cAMP while MDL12330A, an inhibitor of adenylyl cyclase, had weak effect on VASP activation. Knockdown of either Gα13 or RhoA not only suppressed VASP activation, but also ameliorated CuB-induced actin aggregation and abrogated cofilin-actin rod formation. Collectively, our studies highlighted that the CuB-induced actin aggregation and cofilin-actin rod formation was mediated via the Gα13/RhoA/PKA/VASP pathway