Outgoing Transitions Research Articles

Abstract PR008: Cell state transitions drive the evolution of disease progression in B-cell acute lymphoblastic leukemia

Abstract A mathematical framework is constructed to predict the risk of B-lymphoblastic leukemia (B-ALL) relapse post-induction chemotherapy. The framework is a Markov chain model that quantifies spontaneous cell state transitions between distinct immunophenotypic subpopulations defined by CD34 and CD38 expression relative to neutrophils. Cell states are analyzed via flow cytometry pre- and post-treatment, providing insight into the evolution of cell state transition rates during disease progression. Cancer stem cells (CSCs) are hypothesized to promote tumor progression through innate chemoresistance and self-renewal. Ostensible CSCs were first identified in acute myeloid leukemia and were found to have a CD34+/CD38- immunophenotype similar to hematopoietic stem cells. However, the isolation of CSCs from B-ALL has proved more difficult. B-ALL cells with stem cell-like properties have been reported with variable immunophenotype, perhaps due to temporal variation of CD34 and CD38 expression in this setting. We hypothesized that transitions between stem cell-like, hematogone-like, and naive B-cell-like leukemia subpopulations play a significant role in B-ALL disease progression. To test this hypothesis, we trained a Markov chain mathematical model using flow cytometry characterization of four B-ALL cell states with their normal counterpart appearing in parentheses: CD34+/CD38- (hematopoietic stem cells), CD34+/CD38+ (stage 1 hematogones), CD34-/CD38+ (stage 2 and 3 hematogones), and CD34-/CD38- (naïve B-cells). An iterative numerical search procedure was used to derive patient-specific Markov matrices, describing the stochastic cell state transitions. This flow cytometry evaluation was performed on a cohort of patient samples of peripheral blood (N=46) and bone marrow (N=63) with matched clinical features such as BCR::ABL1 status, comprehensive genomic profiling, minimal residual disease (MRD) post-induction chemotherapy, and 3-year relapse. Critical to our goal of quantifying the evolution of state transition rates, we also obtained bone marrow measurements for a cohort of normal/healthy individuals. Patients were divided into post-induction flow MRD positive (N=16), MRD negative (N=30), healthy (N=6) cohorts, as well as relapsed and non-relapsed cohorts to compare features of the transition matrices. Importantly, pre-treatment flow cytometry derived cell state distribution alone is not predictive of relapse or MRD. In contrast, pre-treatment Markov chain transition parameters are found to be clinically predictive of relapse and MRD. MRD correlates to high reciprocity (the product of incoming and outgoing transitions) of the stem cell state. This approach provides supporting evidence that cell state transitions drive B-ALL disease progression. There is an additional strong correlation between Markov transition parameters and both BCR::ABL1 and BCR::ABL1-like B-ALL classification. Finally, comparison of Markov parameters pre- and post-treatment quantifies the evolutionary selection pressures acting on transition rates induced by chemotherapy treatment. Citation Format: Curtis Gravenmier, Ling Zhang, Lynn Moscinski, Jeffrey West. Cell state transitions drive the evolution of disease progression in B-cell acute lymphoblastic leukemia [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr PR008.

Light and heavy particles on a fluctuating surface: Bunchwise balance, irreducible sequences, and local density-height correlations

We study the early time and coarsening dynamics in the Light-Heavy model, a system consisting of two species of particles ($light$ and $heavy$) coupled to a fluctuating surface (described by tilt fields). The dynamics of particles and tilts are coupled through local update rules, and are known to lead to different ordered and disordered steady state phases depending on the microscopic rates. We introduce a generalized balance mechanism in non-equilibrium systems, namely $bunchwise~balance$, in which incoming and outgoing transition currents are balanced between groups of configurations. This allows us to exactly determine the steady state in a subspace of the phase diagram of this model. We introduce the concept of $irreducible~sequences$ of interfaces and bends in this model. These sequences are non-local, and we show that they provide a coarsening length scale in the ordered phases at late times. Finally, we propose a $local$ correlation function ($\mathcal{S}$) that has a direct relation to the number of irreducible sequences, and is able to distinguish between several phases of this system through its coarsening properties. Starting from a totally disordered initial configuration, $\mathcal{S}$ displays an initial linear rise and a broad maximum. As the system evolves towards the ordered steady states, $\mathcal{S}$ further exhibits power law decays at late times that encode coarsening properties of the approach to the ordered phases. Focusing on early time dynamics, we posit coupled mean-field evolution equations governing the particles and tilts, which at short times are well approximated by a set of linearized equations, which we solve analytically. Beyond a timescale set by a lattice cutoff and preceding the onset of coarsening, our linearized theory predicts the existence of an intermediate power-law stretch, which we also find in simulations of the ordered regime of the system.

The Effect of Intensive Margin Changes to Task Content on Employment Dynamics over the Business Cycle

Previous empirical studies investigating the employment impact of technological change have relied on cross-sectional measures of occupational tasks. Here, the author links microdata on individual workers to panel data on occupational tasks while controlling for individual unobservables. In examining the association between routine and abstract tasks and employment transitions, he finds new and economically important evidence that changes to tasks within occupations are strongly related to variation in the transition rates to non-employment and to different occupations. Consistent with recent work focused on technological change during the Great Recession, within-occupation increases in routine tasks are found to increase outgoing transition rates but these effects are concentrated during periods of economic turmoil. The results also show that increases in abstract tasks are associated with decreases in the outgoing transition rates, but this relationship is relatively invariant to business cycle conditions.

Beyond the Click: A First Look at the Role of a Microblogging Platform in the Web Ecosystem

As the largest microblogging service in China, Sina Weibo, is associated with a huge amount of traffic to and from other major websites. Thanks to a massive set of anonymized data from a major operator covering a large-scale metropolitan area, we extract the click-based transitions between Weibo and other websites. Such transitions have not been looked into in most studies that rely on the visible hyper-links among websites. Based on this unique dataset, we show that 38% of the outgoing transitions (leaving Weibo) go to video clip services. Comparatively, links related to news and long videos are clicked less but posted more. This indicates that photograph and text-sharing in microblog have been gradually replaced by video clip sharing. Also, ignoring video clip sharing, 53% of the transitions go to five of the largest Chinese websites, showing how closely connected Weibo has become in the Chinese Web ecosystem. We further look at users’ click behavior in transitions, and find that through co-clustering there do exist a number of prevalent and distinct behavior patterns, suggesting that only seven co-clusters can capture the click behavior of 192 000 studied users. Overall, our work is the first to unveil the significant role of microblogging platforms in the Web ecosystem. Considering the massive user base of Weibo, our findings can aid the design of more personalized link recommendation in Weibo, thus generating more referral traffic, i.e., user visits, from Weibo to other major websites.

Eleventh Hour: The Politics of Policy Initiatives in Presidential Transitions. By David M.Shafie. College Station: Texas A&M University Press, 2013. 244 pp.

Eleventh Hour: The Politics of Policy Initiatives in Presidential Transitions. By David M. Shafie. College Station: Texas A&M University Press, 2013. 244 pp. For those in the cottage industry of presidential transition studies, we wait patiently for years, anticipating a new case to devour. Deprived of a transition to examine in 2012, scholars should savor David Shafie's new book, Eleventh Hour: The Politics of Policy Initiatives in Presidential Transitions. Shafie takes on the oft-discussed but understudied activities of outgoing presidents. Specifically, he presents a series of environmental policy case studies related to late, midnight, or eleventh hour rulemaking drawn from transitions in 1980-81 up to 2008-09. Shafie's writing is clear, and the book extends what we know about this important dimension of the presidency. The authority to make late decisions has long been an option for presidents, but only in the last 30 years has the practice emerged as a favored tactic for Republicans, Democrats, one-term, and two-term presidents, alike. Shafie attributes this to two familiar factors: institutionalization of domestic policy by President Richard Nixon and centralization of policy making under President Ronald Reagan. As opposed to last-minute executive orders or appointments, late rulemaking is an attractive policy strategy because rules are harder to undo by Congress and the incoming administration. It is also a preferred strategy of interest group allies of the president who appreciate the lack of public scrutiny and media attention afforded during the transition period. Despite their popularity, midnight regulations are routinely criticized, including by those who later use the strategy such as incoming Vice President George H. W. Bush. Bush chastised President Jimmy Carter's rulemaking during the 1980 transition. President Bush's (41) perspective is an intriguing one, as he is a participant in one role or another in all five of the transitions studied in the book. Once a critic, Bush later used the strategy during his outgoing transition in 1992-93, as did his son in 2008-09 The strengths of Shafie's book lie in these historical details and the narrative that emerges of environmental policy making since the 1970s. For example, we learn about land management policy in the Department of the Interior and in the Environmental Protection Agency through the lens of regulatory actions in the first and last few days of each administration. Policy change that was unthinkable, or at least politically untenable, for the first three and a half years in office is quickly enacted to open public lands for resource extraction or increase oil pipeline inspections, as the outgoing president celebrates a final Christmas in the White House. …

On the polarization-dependent Raman spectra of aligned carbon nanotubes

We perform polarized Raman spectroscopy on aligned single-walled carbon nanotubes. This test system allows us to empirically address if resonant Raman scattering from on-axis dipole transitions follows a cos2 or a cos4 mosaic spread. We observe in the polar plots a clear cos4 dependence, in agreement with the equivalency of incoming and outgoing dipole transitions.

Stability and robustness of planar switching linear systems

This paper presents a decision algorithm for the analysis of the stability of a class of planar switched linear systems, modeled by hybrid automata. The dynamics in each location of the hybrid automaton is assumed to be linear and asymptotically stable; the guards on the transitions are hyperplanes in the state space. We show that for every pair of an ingoing and an outgoing transition related to a location, the exact gain in the norm of the vector induced by the dynamics in that location can be computed. These exact gains are used in defining a gain automaton which forms the basis of an algorithmic criterion to determine if a planar hybrid automaton is stable or not.

Adiabatic condition and the quantum hitting time of Markov chains

We present an adiabatic quantum algorithm for the abstract problem of searching marked vertices in a graph, or spatial search. Given a random walk (or Markov chain) $P$ on a graph with a set of unknown marked vertices, one can define a related absorbing walk ${P}^{'}$ where outgoing transitions from marked vertices are replaced by self-loops. We build a Hamiltonian $H(s)$ from the interpolated Markov chain $P(s)=(1\ensuremath{-}s)P+{\mathit{sP}}^{'}$ and use it in an adiabatic quantum algorithm to drive an initial superposition over all vertices to a superposition over marked vertices. The adiabatic condition implies that, for any reversible Markov chain and any set of marked vertices, the running time of the adiabatic algorithm is given by the square root of the classical hitting time. This algorithm therefore demonstrates a novel connection between the adiabatic condition and the classical notion of hitting time of a random walk. It also significantly extends the scope of previous quantum algorithms for this problem, which could only obtain a full quadratic speedup for state-transitive reversible Markov chains with a unique marked vertex.

Learning of event-recording automata

In regular inference, a regular language is inferred from answers to a finite set of membership queries, each of which asks whether the language contains a certain word. One of the most well-known regular inference algorithms is the L ∗ algorithm due to Dana Angluin. However, there are almost no extensions of these algorithms to the setting of timed systems. We extend Angluin’s algorithm for on-line learning of regular languages to the setting of timed systems. Since timed automata can freely use an arbitrary number of clocks, we restrict our attention to systems that can be described by deterministic event-recording automata (DERAs). We present three algorithms, T L s g ∗ , T L n s g ∗ and T L s ∗ , for inference of DERAs. In T L s g ∗ and T L n s g ∗ , we further restrict event-recording automata to be event-deterministic in the sense that each state has at most one outgoing transition per action; learning such an automaton becomes significantly more tractable. The algorithm T L n s g ∗ builds on T L s g ∗ , by attempts to construct a smaller (in number of locations) automaton. Finally, T L s ∗ is a learning algorithm for a full class of deterministic event-recording automata, which infers a so called simple DERA, which is similar in spirit to the region graph.

Parallelizing Deadlock Resolution in Symbolic Synthesis of Distributed Programs

Previous work has shown that there are two major complexity barriers in the synthesis of fault-tolerant distributed programs: (1) generation of fault-span, the set of states reachable in the presence of faults, and (2) resolving deadlock states, from where the program has no outgoing transitions. Of these, the former closely resembles with model checking and, hence, techniques for efficient verification are directly applicable to it. Hence, we focus on expediting the latter with the use of multi-core technology. We present two approaches for parallelization by considering different design choices. The first approach is based on the computation of equivalence classes of program transitions (called group computation) that are needed due to the issue of distribution (i.e., inability of processes to atomically read and write all program variables). We show that in most cases the speedup of this approach is close to the ideal speedup and in some cases it is superlinear. The second approach uses traditional technique of partitioning deadlock states among multiple threads. However, our experiments show that the speedup for this approach is small. Consequently, our analysis demonstrates that a simple approach of parallelizing the group computation is likely to be the effective method for using multi-core computing in the context of deadlock resolution.

Grid automata and supervisory control of dense real-time discrete event systems

We present a generalization of the classical supervisory control theory for discrete event systems to a setting of dense real-time systems modeled by Alur and Dill timed automata. The main problem involved is that in general the state space of a timed automaton is (uncountably) infinite. The solution is to reduce the dense time transition system to an appropriate finite discrete subautomaton, the grid automaton, which contains enough information to deal with the timed supervisory control problem (TSCP). The plant and the specifications region graphs are sampled for a granularity defined in a way that each state has an outgoing transition labeled with the same time amount. We redefine the controllability concept in the context of grid automata, and we provide necessary and sufficient solvability conditions under which the optimal solution to centralized supervisory control problems in timed discrete event systems under full observation can be obtained. The enhanced setting admits subsystem composition and the concept of forcible event. A simple example illustrates how the new method can be used to solve the TSCP.

Double Raman resonances by light and heavy magneto-excitons in GaAs/AlAs multiquantum wells

Raman resonance profiles have been measured in GaAs/AlAs multiple quantum wells (MQW's) under an intense magnetic field perpendicular to the layers. We find a strong enhancement of the peak intensities when the difference between the incoming and outgoing transition energies are tuned by the field B to equal the GaAs LO-phonon. This result is interpreted as double Raman resonsnces involving either light-hole or heavy-hole magneto-excitons which differ in 2 units of the Landau index. These observations are better understood by assuming an exciton-phonon scattering mechanism, instead of the usual free electron-phonon interaction.

Reflections on and of the syllable: Does a medial consonant in a VCV belong to the first or second syllable?

Previous research has shown that adaptation effects in speech are position specific: consonant‐vowel (CV) syllables do not affect labeling of vowel‐consonant (VC} syllables, and vice versa. The present study uses this fact to test whether a medial stop consonant in a VCV utterance belongs to the first syllable, the second syllable, or both. Three test series were constructed: one in which the medial consonant was represented by transitions into the stop (/ɑb_ɑ/—/ɑd_ɑ/), one in which the transitions were out of the stop (/ɑ_bɑ/—/ɑ_dɑ/), and one with both incoming and outgoing transitions (ɑbbɑ/—/ɑddɑ/). Adaptation with /bɑ/, /ɑb/, /ɑ_bɑ/, /ɑb_ɑ/, and /ɑbbɑ/ was conducted on all three continua. The pattern of results is used to address the syllabification issue, and the acoustic‐phonetic issue which has been discussed in the adaptation literature.