Department Seminars & Colloquia

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Chronotherapeutics- that is administering drugs following the patient’s biological rhythms over the 24 h span- may largely impact on both drug toxicities and efficacy in various pathologies including cancer [1]. However, recent findings highlight the critical need of personalizing circadian delivery according to the patient sex, genetic background or chronotype. Chronotherapy personalization requires to reliably account for the temporal dynamics of molecular pathways of patient’s response to drug administration [2]. In a context where clinical molecular data is usually minimal in individual patients, multi-scale- from preclinical to clinical- systems pharmacology stands as an adapted solution to describe gene and protein networks driving circadian rhythms of treatment efficacy and side effects and allow for the design of personalized chronotherapies. Such a multiscale approach is being undertaken for personalizing the circadian administration of irinotecan, one of the cornerstones of chemotherapies against digestive cancers. Irinotecan molecular chronopharmacology was studied at the cellular level in an in vitro/in silico investigation. Large transcription rhythms of period T= 28 h 06 min (SD 1 h 41 min) moderated drug bioactivation, detoxification, transport, and target in synchronized Caco-2 colorectal cancer cell cultures. These molecular rhythms translated into statistically significant changes according to drug timing in irinotecan pharmacokinetics, pharmacodynamics, and drug-induced apoptosis. Clock silencing through siBMAL1 exposure ablated all the chronopharmacology mechanisms. Mathematical modeling highlighted circadian bioactivation and detoxification as the most critical determinants of irinotecan chronopharmacology [3]. The cellular model of irinotecan chronoPK-PD was further tested on SW480 and SW620 cell lines, and connected to a new clock model to investigate the feasibility of irinotecan timing personalization solely based on clock gene expression monitoring (Hesse, Martinelli et al., under review). To step towards the clinics, on one side, mathematical models of irinotecan, oxaliplatin and 5-fluorouracil pharmacokinetics were designed to precisely compute the exposure concentration of tissue over time after complex chronomodulated drug administration through programmable pumps [4]. On the other side, we aimed to design a model learning methodology predicting from non-invasively measured circadian biomarkers (e.g. rest-activity, body temperature, cortisol, food intake, melatonin), the patient peripheral circadian clocks and associated optimal drug timing [5]. We investigated at the molecular scale the influence of systemic regulators on peripheral clocks in four classes of mice (2 strains, 2 sexes). Best models involved a modulation of either Bmal1 or Per2 transcription most likely by temperature or nutrient exposure cycles. The strengths of systemic regulations were found to be significantly different according to mouse sex and genetic background. References 1. Ballesta, A., et al., Systems Chronotherapeutics. Pharmacol Rev, 2017. 69(2): p. 161-199. 2. Sancar, A. and R.N. Van Gelder, Clocks, cancer, and chronochemotherapy. Science, 2021. 371(6524). 3. Dulong, S., et al., Identification of Circadian Determinants of Cancer Chronotherapy through In Vitro Chronopharmacology and Mathematical Modeling. Mol Cancer Ther, 2015. 4. Hill, R.J.W., et al., Optimizing circadian drug infusion schedules towards personalized cancer chronotherapy. PLoS Comput Biol, 2020. 16(1): p. e1007218. 5. Martinelli, J., et al., Model learning to identify systemic regulators of the peripheral circadian clock. 2021.
This talk will be presented online. Zoom link: 709 120 4849 (pw: 1234)
Bouchet (1987) defined delta-matroids by relaxing the base exchange axiom of matroids. Oum (2009) introduced a graphic delta-matroid from a pair of a graph and its vertex subset. We define a $\Gamma$-graphic delta-matroid for an abelian group $\Gamma$, which generalizes a graphic delta-matroid. For an abelian group $\Gamma$, a $\Gamma$-labelled graph is a graph whose vertices are labelled by elements of $\Gamma$. We prove that a certain collection of edge sets of a $\Gamma$-labelled graph forms a delta-matroid, which we call a $\Gamma$-graphic delta-matroid, and provide a polynomial-time algorithm to solve the separation problem, which allows us to apply the symmetric greedy algorithm of Bouchet (1987) to find a maximum weight feasible set in such a delta-matroid. We also prove that a $\Gamma$-graphic delta-matroid is a graphic delta-matroid if and only if it is even. We prove that every $\mathbb{Z}_p^k$-graphic delta matroid is represented by some symmetric matrix over a field of characteristic of order $p^k$, and if every $\Gamma$-graphic delta-matroid is representable over a finite field $\mathbb{F}$, then $\Gamma$ is isomorphic to $\mathbb{Z}_p^k$ and $\mathbb{F}$ is a field of order $p^\ell$ for some prime $p$ and positive integers $k$ and $\ell$. This is joint work with Duksang Lee and Sang-il Oum.
Host: Sang-il Oum     English     2021-10-23 20:50:37
Within a given species, fluctuations in egg or embryo size is unavoidable. Despite this, the gene expression pattern and hence the embryonic structure often scale in proportion with the body length. This scaling phenomenon is very common in development and regeneration and has long fascinated scientists. I will first discuss a generic theoretical framework to show how scaling gene expression pattern can emerge from non-scaling morphogen gradients. I will then demonstrate that the Drosophila gap gene system achieves scaling in a way that is entirely consistent with our theory. Remarkably, a parameter-free model based on the theory quantitatively accounts for the gap gene expression pattern in nearly all morphogen mutants. Furthermore, the regulation logic and the coding/decoding strategy of the gap gene system can be revealed. Our work provides a general theoretical framework on a large class of problems where scaling output is induced by non-scaling input, as well as a unified understanding of scaling, mutants’ behavior and regulation in the Drosophila gap gene and related systems.
This talk will be presented online. Zoom link: 709 120 4849 (pw: 1234)
Majority dynamics on a graph $G$ is a deterministic process such that every vertex updates its $\pm 1$-assignment according to the majority assignment on its neighbor simultaneously at each step. Benjamini, Chan, O'Donnell, Tamuz and Tan conjectured that, in the Erd\H{o}s--R\'enyi random graph $G(n,p)$, the random initial $\pm 1$-assignment converges to a $99\%$-agreement with high probability whenever $p=\omega(1/n)$. This conjecture was first confirmed for $p\geq\lambda n^{-1/2}$ for a large constant $\lambda$ by Fountoulakis, Kang and Makai. Although this result has been reproved recently by Tran and Vu and by Berkowitz and Devlin, it was unknown whether the conjecture holds for $p< \lambda n^{-1/2}$. We break this $\Omega(n^{-1/2})$-barrier by proving the conjecture for sparser random graphs $G(n,p)$, where $\lambda' n^{-3/5}\log n \leq p \leq \lambda n^{-1/2}$ with a large constant $\lambda'>0$.
Host: Sang-il Oum     English     2021-09-22 08:28:45
Immune sentinel cells must initiate the appropriate immune response upon sensing the presence of diverse pathogens or immune stimuli. To generate stimulus-specific gene expression responses, immune sentinel cells have evolved a temporal code in the dynamics of stimulus responsive transcription factors. I will present recent works 1) using an information theoretic approach to identify the codewords, termed “signaling codons”, 2) using a machine learning approach to characterize their reliability and points of confusion, and 3) dynamical systems modeling to characterize the molecular circuits that allow for their encoding. I will present progress on how the temporal code may be decoded to specify immune responses. Further, I will discuss to what extent such a code may be harnessed to achieve greater pharmacological specificity when therapeutically targeting pleiotropic signaling hubs. NFκB Signaling: information theory, signaling codons
This talk will be presented online. Zoom link: 709 120 4849 (pw: 1234)
I am going to present an algorithm for computing a feedback vertex set of a unit disk graph of size k, if it exists, which runs in time $2^{O(\sqrt{k})}(n + m)$, where $n$ and $m$ denote the numbers of vertices and edges, respectively. This improves the $2^{O(\sqrt{k}\log k)}(n + m)$-time algorithm for this problem on unit disk graphs by Fomin et al. [ICALP 2017].
Host: Sang-il Oum     English     2021-09-22 08:25:36
The extremal function $c(H)$ of a graph $H$ is the supremum of densities of graphs not containing $H$ as a minor, where the density of a graph is the ratio of the number of edges to the number of vertices. Myers and Thomason (2005), Norin, Reed, Thomason and Wood (2020), and Thomason and Wales (2019) determined the asymptotic behaviour of $c(H)$ for all polynomially dense graphs $H$, as well as almost all graphs of constant density. We explore the asymptotic behavior of the extremal function in the regime not covered by the above results, where in addition to having constant density the graph $H$ is in a graph class admitting strongly sublinear separators. We establish asymptotically tight bounds in many cases. For example, we prove that for every planar graph $H$, \[c(H) = (1+o(1))\max (v(H)/2, v(H)-\alpha(H)),\] extending recent results of Haslegrave, Kim and Liu (2020). Joint work with Sergey Norin and David R. Wood.
Host: Sang-il Oum     To be announced     2021-09-02 08:55:46
A particularly important substructure in modeling joint linear chance-constrained programs with random right-hand sides and finite sample space is the intersection of mixing sets with common binary variables (and possibly a knapsack constraint). In this talk, we first explain basic mixing sets by establishing a strong and previously unrecognized connection to submodularity. In particular, we show that mixing inequalities with binary variables are nothing but the polymatroid inequalities associated with a specific submodular function. This submodularity viewpoint enables us to unify and extend existing results on valid inequalities and convex hulls of the intersection of multiple mixing sets with common binary variables. Then, we study such intersections under an additional linking constraint lower bounding a linear function of the continuous variables. This is motivated from the desire to exploit the information encoded in the knapsack constraint arising in joint linear CCPs via the quantile cuts. We propose a new class of valid inequalities and characterize when this new class along with the mixing inequalities are sufficient to describe the convex hull. This is based on joint work with Fatma Fatma Kılınç-Karzan and Simge Küçükyavuz.
Host: Sang-il Oum     English     2021-09-02 08:53:43