Cytotoxic CD4+ T cells in patients with B cell chronic lymphocytic leukemia kill via a perforin-mediated pathway

Background and Objectives: B-cell chronic lymphocytic leukemia (B-CLL) is a clonal expansion of CD5+B cells that accumulate due to their uncontrolled growth and resistance to apoptosis. We have previously shown that up to 50% of blood CD4+ T cells in BCLL patients have a cytotoxicity-related CD28-CD57+ phenotype and high content of both granzyme B and perforin (PF). In this study we investigate the cytotoxic potential of these cells against autologous B-CLL cells. Design and Methods: Blood CD4+ or CD8+ T cells were positively isolated from B-CLL patients and cultured under a range of conditions with autologous purified B-CLL cells and with bispecific [anti-CD3 x anti-CD19] antibodies. Apoptosis of labeled B-CLL cells was assessed using the change of mitochondrial membrane potential with the fluorescent dye DiOC6 and confirmed by annexin V binding. Results: There was time- and dose-dependent killing of B-CLL cells by both CD8+ and CD4+ T cells and this ranged from 6.6 - 68.0% for CD4+ cells and 6.4 - 57.8% for CD8+ cells. Almost complete inhibition by concanamycin A suggests that CD4+ T cells like CD8+ T cells induced apoptosis through a perforin-mediated pathway, but not via Fas/FasL (as indicated by lack of blocking with brefeldin A), tumor necrosis factor or TRAIL. Interpretation and Conclusions: This study shows that blood CD4+PF+ T cells enriched in B-CLL patients, are able to kill autologous B-CLL cells ex vivo, through bispecific antibodies via a perforin mediated mechanism

Exclusion statistics: A resolution of the problem of negative weights

We give a formulation of the single particle occupation probabilities for a system of identical particles obeying fractional exclusion statistics of Haldane. We first derive a set of constraints using an exactly solvable model which describes an ideal exclusion statistics system and deduce the general counting rules for occupancy of states obeyed by these particles. We show that the problem of negative probabilities may be avoided with these new counting rules.Comment: REVTEX 3.0, 14 page

BPS R-balls in N=4 SYM on R X S^3, Quantum Hall Analogy and AdS/CFT Holography

In this paper, we propose a new approach to study the BPS dynamics in N=4 supersymmetric U(N) Yang-Mills theory on R X S^3, in order to better understand the emergence of gravity in the gauge theory. Our approach is based on supersymmetric, space-filling Q-balls with R-charge, which we call R-balls. The usual collective coordinate method for non-topological scalar solitons is applied to quantize the half and quarter BPS R-balls. In each case, a different quantization method is also applied to confirm the results from the collective coordinate quantization. For finite N, the half BPS R-balls with a U(1) R-charge have a moduli space which, upon quantization, results in the states of a quantum Hall droplet with filling factor one. These states are known to correspond to the ``sources'' in the Lin-Lunin-Maldacena geometries in IIB supergravity. For large N, we find a new class of quarter BPS R-balls with a non-commutativity parameter. Quantization on the moduli space of such R-balls gives rise to a non-commutative Chern-Simons matrix mechanics, which is known to describe a fractional quantum Hall system. In view of AdS/CFT holography, this demonstrates a profound connection of emergent quantum gravity with non-commutative geometry, of which the quantum Hall effect is a special case.Comment: 42 pages, 2 figures; v3: a new paragraph on counting unbroken susy of NC R-balls and references adde

One-way multigrid method in electronic structure calculations

We propose a simple and efficient one-way multigrid method for self-consistent electronic structure calculations based on iterative diagonalization. Total energy calculations are performed on several different levels of grids starting from the coarsest grid, with wave functions transferred to each finer level. The only changes compared to a single grid calculation are interpolation and orthonormalization steps outside the original total energy calculation and required only for transferring between grids. This feature results in a minimal amount of code change, and enables us to employ a sophisticated interpolation method and noninteger ratio of grid spacings. Calculations employing a preconditioned conjugate gradient method are presented for two examples, a quantum dot and a charged molecular system. Use of three grid levels with grid spacings 2h, 1.5h, and h decreases the computer time by about a factor of 5 compared to single level calculations.Comment: 10 pages, 2 figures, to appear in Phys. Rev. B, Rapid Communication

Structure Formation, Melting, and the Optical Properties of Gold/DNA Nanocomposites: Effects of Relaxation Time

We present a model for structure formation, melting, and optical properties of gold/DNA nanocomposites. These composites consist of a collection of gold nanoparticles (of radius 50 nm or less) which are bound together by links made up of DNA strands. In our structural model, the nanocomposite forms from a series of Monte Carlo steps, each involving reaction-limited cluster-cluster aggregation (RLCA) followed by dehybridization of the DNA links. These links form with a probability $p_{eff}$ which depends on temperature and particle radius $a$. The final structure depends on the number of monomers (i. e. gold nanoparticles) $N_m$, $T$, and the relaxation time. At low temperature, the model results in an RLCA cluster. But after a long enough relaxation time, the nanocomposite reduces to a compact, non-fractal cluster. We calculate the optical properties of the resulting aggregates using the Discrete Dipole Approximation. Despite the restructuring, the melting transition (as seen in the extinction coefficient at wavelength 520 nm) remains sharp, and the melting temperature $T_M$ increases with increasing $a$ as found in our previous percolation model. However, restructuring increases the corresponding link fraction at melting to a value well above the percolation threshold. Our calculated extinction cross section agrees qualitatively with experiments on gold/DNA composites. It also shows a characteristic ``rebound effect,'' resulting from incomplete relaxation, which has also been seen in some experiments. We discuss briefly how our results relate to a possible sol-gel transition in these aggregates.Comment: 12 pages, 10 figure

Quantum Cryptography Using Single Particle Entanglement

A quantum cryptography scheme based on entanglement between a single particle state and a vacuum state is proposed. The scheme utilizes linear optics devices to detect the superposition of the vacuum and single particle states. Existence of an eavesdropper can be detected by using a variant of Bell's inequality.Comment: 4 pages, 3figures, revte

Nonfactorizable contributions to B→D(∗)MB \to D^{(*)} M decays

While the factorization assumption works well for many two-body nonleptonic $B$ meson decay modes, the recent measurement of $\bar B\to D^{(*)0}M^0$ with $M=\pi$, $\rho$ and $\omega$ shows large deviation from this assumption. We analyze the $B\to D^{(*)}M$ decays in the perturbative QCD approach based on $k_T$ factorization theorem, in which both factorizable and nonfactorizable contributions can be calculated in the same framework. Our predictions for the Bauer-Stech-Wirbel parameters, $|a_2/a_1|= 0.43\pm 0.04$ and $Arg(a_2/a_1)\sim -42^\circ$ and $|a_2/a_1|= 0.47\pm 0.05$ and $Arg(a_2/a_1)\sim -41^\circ$, are consistent with the observed $B\to D\pi$ and $B\to D^*\pi$ branching ratios, respectively. It is found that the large magnitude $|a_2|$ and the large relative phase between $a_2$ and $a_1$ come from color-suppressed nonfactorizable amplitudes. Our predictions for the ${\bar B}^0\to D^{(*)0}\rho^0$, $D^{(*)0}\omega$ branching ratios can be confronted with future experimental data.Comment: 25 pages with Latex, axodraw.sty, 6 figures and 5 tables, Version published in PRD, Added new section 5 and reference

Impact of additional genetic abnormalities at diagnosis of chronic myeloid leukemia for first-line imatinib-treated patients receiving proactive treatment intervention

Early view: March 23, 2023The BCR::ABL1 gene fusion initiates chronic myeloid leukemia (CML), however evidence has accumulated from studies of highly selected cohorts that variants in other cancer-related genes are associated with treatment failure. Nevertheless, the true incidence and impact of additional genetic abnormalities (AGAs) at diagnosis of chronic phase (CP)-CML is unknown. We sought to determine whether AGAs at diagnosis in a consecutive imatinib-treated cohort of 210 patients enrolled in the TIDEL-II trial influenced outcome despite a highly proactive treatment intervention strategy. Survival outcomes including overall survival, progression-free survival, failure-free survival and BCR::ABL1 kinase domain mutation acquisition were evaluated. Molecular outcomes were measured at a central laboratory and included major molecular response (MMR, BCR::ABL1 ≤0.1%IS), MR4 (BCR::ABL1 ≤0.01%IS) and MR4.5 (BCR::ABL1 ≤0.0032%IS). AGAs included variants in known cancer genes and novel rearrangements involving the formation of the Philadelphia chromosome. Clinical outcomes and molecular response were assessed based on the genetic profile and other baseline factors. AGAs were identified in 31% of patients. Potentially pathogenic variants in cancer-related genes were detected in 16% of patients at diagnosis (including gene fusions and deletions) and structural rearrangements involving the Philadelphia chromosome (Ph-associated rearrangements), detected in 18%. Multivariable analysis demonstrated that the combined genetic abnormalities plus the ELTS clinical risk score were independent predictors of lower molecular response rates and higher treatment failure. Despite a highly proactive treatment intervention strategy, first-line imatinib-treated patients with AGAs had poorer response rates. This data provides evidence for the incorporation of genomically-based risk assessment for CML.Naranie Shanmuganathan, Carol Wadham, NurHezrin Shahrin, Jinghua Feng, Daniel Thomson, Paul Wang, Verity Saunders, Chung Hoow Kok, Rob M. King, Rosalie R. Kenyon, Ming Lin, Ilaria S. Pagani, David M. Ross, Agnes S.M. Yong, Andrew P. Grigg, Anthony K. Mills, Anthony P. Schwarer, Jodi Braley, Haley Altamura, David T. Yeung, Hamish S. Scott, Andreas W. Schreiber, Timothy P. Hughes and Susan Branfor

Horizontal Branch Stars: The Interplay between Observations and Theory, and Insights into the Formation of the Galaxy

We review HB stars in a broad astrophysical context, including both variable and non-variable stars. A reassessment of the Oosterhoff dichotomy is presented, which provides unprecedented detail regarding its origin and systematics. We show that the Oosterhoff dichotomy and the distribution of globular clusters (GCs) in the HB morphology-metallicity plane both exclude, with high statistical significance, the possibility that the Galactic halo may have formed from the accretion of dwarf galaxies resembling present-day Milky Way satellites such as Fornax, Sagittarius, and the LMC. A rediscussion of the second-parameter problem is presented. A technique is proposed to estimate the HB types of extragalactic GCs on the basis of integrated far-UV photometry. The relationship between the absolute V magnitude of the HB at the RR Lyrae level and metallicity, as obtained on the basis of trigonometric parallax measurements for the star RR Lyrae, is also revisited, giving a distance modulus to the LMC of (m-M)_0 = 18.44+/-0.11. RR Lyrae period change rates are studied. Finally, the conductive opacities used in evolutionary calculations of low-mass stars are investigated. [ABRIDGED]Comment: 56 pages, 22 figures. Invited review, to appear in Astrophysics and Space Scienc

The Physics of Star Cluster Formation and Evolution

© 2020 Springer-Verlag. The final publication is available at Springer via https://doi.org/10.1007/s11214-020-00689-4.Star clusters form in dense, hierarchically collapsing gas clouds. Bulk kinetic energy is transformed to turbulence with stars forming from cores fed by filaments. In the most compact regions, stellar feedback is least effective in removing the gas and stars may form very efficiently. These are also the regions where, in high-mass clusters, ejecta from some kind of high-mass stars are effectively captured during the formation phase of some of the low mass stars and effectively channeled into the latter to form multiple populations. Star formation epochs in star clusters are generally set by gas flows that determine the abundance of gas in the cluster. We argue that there is likely only one star formation epoch after which clusters remain essentially clear of gas by cluster winds. Collisional dynamics is important in this phase leading to core collapse, expansion and eventual dispersion of every cluster. We review recent developments in the field with a focus on theoretical work.Peer reviewe