Effects of multiple-dose ponesimod, a selective SIP1 receptor modulator, on lymphocyte subsets in healthy humans

This study investigated the effects of ponesimod, a selective SIP1 receptor modulator, on T lymphocyte subsets in 16 healthy subjects. Lymphocyte subset proportions and absolute numbers were determined at baseline and on Day 10, after once-daily administration of ponesimod (10 mg, 20 mg, and 40 mg each consecutively for 3 days) or placebo (ratio 3: 1). The overall change from baseline in lymphocyte count was -1,292 +/- 340x10(6) cells/L and 275 +/- 486x10(6) cells/L in ponesimod- and placebo-treated subjects, respectively. This included a decrease in both T and B lymphocytes following ponesimod treatment. A decrease in naive CD4(+) T cells (CD45RA(+)CCR7(+)) from baseline was observed only after ponesimod treatment (-113 +/- 98x10(6) cells/L, placebo: 0 +/- 18x10(6) cells/L). The number of T-cytotoxic (CD3(+)CD8(+)) and T-helper (CD3(+)CD4(+)) cells was significantly altered following ponesimod treatment compared with placebo. Furthermore, ponesimod treatment resulted in marked decreases in CD4(+) T-central memory (CD45RA(-)CCR7(+)) cells (-437 +/- 164x10(6) cells/L) and CD4(+) T-effector memory (CD45RA(-)CCR7(-)) cells (-131 +/- 57x10(6) cells/L). In addition, ponesimod treatment led to a decrease of -228 +/- 90x10(6) cells/L of gut-homing T cells (CLA(-)integrin beta 7(+)). In contrast, when compared with placebo, CD8(+) T-effector memory and natural killer (NK) cells were not significantly reduced following multiple-dose administration of ponesimod. In summary, ponesimod treatment led to a marked reduction in overall T and B cells. Further investigations revealed that the number of CD4(+) cells was dramatically reduced, whereas CD8(+) and NK cells were less affected, allowing the body to preserve critical viral-clearing functions

Natural Complexity, Computational Complexity and Depth

Depth is a complexity measure for natural systems of the kind studied in statistical physics and is defined in terms of computational complexity. Depth quantifies the length of the shortest parallel computation required to construct a typical system state or history starting from simple initial conditions. The properties of depth are discussed and it is compared to other complexity measures. Depth can only be large for systems with embedded computation.Comment: 21 pages, 1 figur

Parallel Algorithm and Dynamic Exponent for Diffusion-limited Aggregation

A parallel algorithm for ``diffusion-limited aggregation'' (DLA) is described and analyzed from the perspective of computational complexity. The dynamic exponent z of the algorithm is defined with respect to the probabilistic parallel random-access machine (PRAM) model of parallel computation according to $T \sim L^{z}$, where L is the cluster size, T is the running time, and the algorithm uses a number of processors polynomial in L\@. It is argued that z=D-D_2/2, where D is the fractal dimension and D_2 is the second generalized dimension. Simulations of DLA are carried out to measure D_2 and to test scaling assumptions employed in the complexity analysis of the parallel algorithm. It is plausible that the parallel algorithm attains the minimum possible value of the dynamic exponent in which case z characterizes the intrinsic history dependence of DLA.Comment: 24 pages Revtex and 2 figures. A major improvement to the algorithm and smaller dynamic exponent in this versio

Pair-correlation Kinetics and the Reversible Diffusion-controlled Reaction

It has long been known that the time course of a bimolecular reaction occurring in a condensed host depends on the behavior of the nonequilibrium pair-correlation function for reactant pairs. The classical analysis of such reactions has led to a kind of standard rule: The association rate constant for a diffusion-controlled reaction is 4πDR and this rate constant produces the fastest possible kinetics. This result is only (approximately) true for the case of an irreversible reaction, however. Here, we reexamine this old problem, looking closely at the reversible case. We report a result that challenges the standard wisdom: When the reaction is highly reversible the relaxation of the related kinetics to equilibrium can be much faster than the model in which 4πDR is the association rate constant. We suggest that our work provides a natural resolution to a well-known, long-standing controversy in the study of electrically active impurities in silicon grown by the Czochralski method

The Computational Complexity of Generating Random Fractals

In this paper we examine a number of models that generate random fractals. The models are studied using the tools of computational complexity theory from the perspective of parallel computation. Diffusion limited aggregation and several widely used algorithms for equilibrating the Ising model are shown to be highly sequential; it is unlikely they can be simulated efficiently in parallel. This is in contrast to Mandelbrot percolation that can be simulated in constant parallel time. Our research helps shed light on the intrinsic complexity of these models relative to each other and to different growth processes that have been recently studied using complexity theory. In addition, the results may serve as a guide to simulation physics.Comment: 28 pages, LATEX, 8 Postscript figures available from [email protected]

Multi-static, multi-frequency scattering from zooplankton

Abstract: Inversion of multi-frequency acoustic backscattering cm be used to estkate size-abundances of zooplankton, given a valid model for backscattering for the zooplankters. me physical properties of the scatterers, density and compressibility (or compressional-wave sound speed), are usually assigned fixed values in the scattering model.~ese properties wotid be of interest if they could be mew~~in~it~, e.g.to exm~e~hange$in liPid contents over seasons. Extension of currently-favored backscattering models to multi-static configurations looks promising as a method to directly measure these relevant physical properties simultaneously with size-abundance estimation

Time-Lock Puzzles from Randomized Encodings

Time-lock puzzles are a mechanism for sending messages "to the future". A sender can quickly generate a puzzle with a solution s that remains hidden until a moderately large amount of time t has elapsed. The solution s should be hidden from any adversary that runs in time significantly less than t, including resourceful parallel adversaries with polynomially many processors. While the notion of time-lock puzzles has been around for 22 years, there has only been a single candidate proposed. Fifteen years ago, Rivest, Shamir and Wagner suggested a beautiful candidate time-lock puzzle based on the assumption that exponentiation modulo an RSA integer is an "inherently sequential" computation. We show that various flavors of randomized encodings give rise to time-lock puzzles of varying strengths, whose security can be shown assuming the mere existence of non-parallelizing languages, which are languages that require circuits of depth at least t to decide, in the worst-case. The existence of such languages is necessary for the existence of time-lock puzzles. We instantiate the construction with different randomized encodings from the literature, where increasingly better efficiency is obtained based on increasingly stronger cryptographic assumptions, ranging from one-way functions to indistinguishability obfuscation. We also observe that time-lock puzzles imply one-way functions, and thus the reliance on some cryptographic assumption is necessary. Finally, generalizing the above, we construct other types of puzzles such as proofs of work from randomized encodings and a suitable worst-case hardness assumption (that is necessary for such puzzles to exist)

Dental attendance, restoration and extractions in adults with intellectual disabilities compared with the general population: a record linkage study

Background: Oral health may be poorer in adults with intellectual disabilities (IDs) who rely on carer support and medications with increased dental risks. Methods: Record linkage study of dental outcomes, and associations with anticholinergic (e.g. antipsychotics) and sugar‐containing liquid medication, in adults with IDs compared with age–sex–neighbourhood deprivation‐matched general population controls. Results: A total of 2933/4305 (68.1%) with IDs and 7761/12 915 (60.1%) without IDs attended dental care: odds ratio (OR) = 1.42 [1.32, 1.53]; 1359 (31.6%) with IDs versus 5233 (40.5%) without IDs had restorations: OR = 0.68 [0.63, 0.73]; and 567 (13.2%) with IDs versus 2048 (15.9%) without IDs had dental extractions: OR = 0.80 [0.73, 0.89]. Group differences for attendance were greatest in younger ages, and restoration/extractions differences were greatest in older ages. Adults with IDs were more likely prescribed with anticholinergics (2493 (57.9%) vs. 6235 (48.3%): OR = 1.49 [1.39, 1.59]) and sugar‐containing liquids (1641 (38.1%) vs. 2315 (17.9%): OR = 2.89 [2.67, 3.12]). Conclusion: Carers support dental appointments, but dentists may be less likely to restore teeth, possibly extracting multiple teeth at individual appointments instead