309 research outputs found
Mathematical modeling reveals threshold mechanism in CD95-induced apoptosis
Mathematical modeling is required for understanding the complex behavior of large signal transduction networks. Previous attempts to model signal transduction pathways were often limited to small systems or based on qualitative data only. Here, we developed a mathematical modeling framework for understanding the complex signaling behavior of CD95(APO-1/Fas)-mediated apoptosis. Defects in the regulation of apoptosis result in serious diseases such as cancer, autoimmunity, and neurodegeneration. During the last decade many of the molecular mechanisms of apoptosis signaling have been examined and elucidated. A systemic understanding of apoptosis is, however, still missing. To address the complexity of apoptotic signaling we subdivided this system into subsystems of different information qualities. A new approach for sensitivity analysis within the mathematical model was key for the identification of critical system parameters and two essential system properties: modularity and robustness. Our model describes the regulation of apoptosis on a systems level and resolves the important question of a threshold mechanism for the regulation of apoptosis
Opportunities and Challenges: Hepatitis C Testing and Treatment Access Experiences Among People in Methadone and Buprenorphine Treatment During COVID-19, Arizona, 2021
Introduction: The purpose of this study was to characterize hepatitis C virus screening and treatment access experiences among people in treatment for opioid use disorder in Arizona during COVID-19. Methods: Arizonans receiving treatment for opioid use disorder from methadone clinics and buprenorphine providers during COVID-19 were interviewed about hepatitis C virus testing, curative treatment, and knowledge about screening recommendations. Interviews were conducted with 121 people from August 4, 2021 to October 10, 2021. Qualitative data were coded using the categories of hepatitis C virus testing, knowledge of screening recommendations, diagnosis, and experiences seeking curative treatment. Data were also quantitated for bivariate testing with outcome variables of last hepatitis C virus test, diagnosis, and curative treatment process. Findings were arrayed along an adapted hepatitis C virus cascade framework to inform program and policy improvements. Results: Just over half of the sample reported ever having tested for hepatitis C virus (51.2%, n=62) and of this group, 58.1% were tested in the past 12 months. Among those who were ever tested, 54.8% reported a hepatitis C virus diagnosis and 16.1% reported either being in treatment or having been declared cured of the hepatitis C virus. Among those who were diagnosed with hepatitis C, 14.7% indicated that they unsuccessfully tried to access curative treatment and would not attempt to again. Reasons cited for not accessing or receiving curative treatment included beliefs about treatment safety, barriers created by access requirements, natural resolution of the infection, and issues with healthcare coverage and authorization. Conclusions: Structural barriers continue to prevent curative hepatitis C virus treatment access. Given that methadone and buprenorphine treatment providers serve patients who are largely undiagnosed or treated for hepatitis C virus, opportunities exist for them to screen their patients regularly and provide support for and/or navigation to hepatitis C virus curative treatment
Bistability in Apoptosis by Receptor Clustering
Apoptosis is a highly regulated cell death mechanism involved in many
physiological processes. A key component of extrinsically activated apoptosis
is the death receptor Fas, which, on binding to its cognate ligand FasL,
oligomerize to form the death-inducing signaling complex. Motivated by recent
experimental data, we propose a mathematical model of death ligand-receptor
dynamics where FasL acts as a clustering agent for Fas, which form locally
stable signaling platforms through proximity-induced receptor interactions.
Significantly, the model exhibits hysteresis, providing an upstream mechanism
for bistability and robustness. At low receptor concentrations, the bistability
is contingent on the trimerism of FasL. Moreover, irreversible bistability,
representing a committed cell death decision, emerges at high concentrations,
which may be achieved through receptor pre-association or localization onto
membrane lipid rafts. Thus, our model provides a novel theory for these
observed biological phenomena within the unified context of bistability.
Importantly, as Fas interactions initiate the extrinsic apoptotic pathway, our
model also suggests a mechanism by which cells may function as bistable
life/death switches independently of any such dynamics in their downstream
components. Our results highlight the role of death receptors in deciding cell
fate and add to the signal processing capabilities attributed to receptor
clustering.Comment: Accepted by PLoS Comput Bio
An exploratory investigation of brain collateral circulation plasticity after cerebral ischemia in two experimental C57BL/6 mouse models
Brain collateral circulation is an essential compensatory mechanism in response to acute brain ischemia. To study the temporal evolution of brain macro and microcollateral recruitment and their reciprocal interactions in response to different ischemic conditions, we applied a combination of complementary techniques (T2-weighted magnetic resonance imaging [MRI], time of flight [TOF] angiography [MRA], cerebral blood flow [CBF] imaging and histology) in two different mouse models. Hypoperfusion was either induced by permanent bilateral common carotid artery stenosis (BCCAS) or 60-min transient unilateral middle cerebral artery occlusion (MCAO). In both models, collateralization is a very dynamic phenomenon with a global effect affecting both hemispheres. Patency of ipsilateral posterior communicating artery (PcomA) represents the main variable survival mechanism and the main determinant of stroke lesion volume and recovery in MCAO, whereas the promptness of external carotid artery retrograde flow recruitment together with PcomA patency, critically influence survival, brain ischemic lesion volume and retinopathy in BCCAS mice. Finally, different ischemic gradients shape microcollateral density and size
Amici Curiae Brief of New York law school professors in People v. Harris: Constitutionality of the New York Death Penalty Statute Under the State Constitution\u27s Cruel and Unusual Punishments and Antidiscrimination Clauses
Amici are teachers in New York law schools who have studied the operation of the death penalty for the purpose of teaching the subject, writing about it in scholarly journals, or representing persons accused or convicted of capital crimes. Most of us have worked in the field both as academics and as pro bono counsel for condemned inmates. Collectively, we have had first-hand experience in hundreds of death cases, in dozens of jurisdictions, extending over more than a third of a century.
Our experience has convinced us that capital punishment cannot be administered with the fairness, reliability, and freedom from discrimination that a penalty so grave and irreversible requires. This is no accident or transitory condition; it is the consequence of certain innate attributes of the penalty of death. The purpose of our brief is to analyze those attributes and explain why they are fundamentally at war with the Cruel and Unusual Punishments Clause and the Antidiscrimination Clause of New York’s Bill of Rights. We hope to persuade the Court that it should not temporize with the death penalty in the face of this basic incompatibility but should hold the 1995 death penalty statute altogether unconstitutional
External Control of the GAL Network in S. cerevisiae: A View from Control Theory
While there is a vast literature on the control systems that cells utilize to regulate their own state, there is little published work on the formal application of control theory to the external regulation of cellular functions. This paper chooses the GAL network in S. cerevisiae as a well understood benchmark example to demonstrate how control theory can be employed to regulate intracellular mRNA levels via extracellular galactose. Based on a mathematical model reduced from the GAL network, we have demonstrated that a galactose dose necessary to drive and maintain the desired GAL genes' mRNA levels can be calculated in an analytic form. And thus, a proportional feedback control can be designed to precisely regulate the level of mRNA. The benefits of the proposed feedback control are extensively investigated in terms of stability and parameter sensitivity. This paper demonstrates that feedback control can both significantly accelerate the process to precisely regulate mRNA levels and enhance the robustness of the overall cellular control system
Industrial Structure and Political Outcomes: The Case of the 2016 US Presidential Election
This paper analyzes the US presidential election of 2016, examining the patterns of industrial structure and party competition in both the major party primaries and the general election. It attempts to identify the new, historically specific factors that led to the upheavals, especially the steady growth of a “dual economy” that locks more and more Americans out of the middle class. It draws extensively on a newly assembled, more comprehensive database to identify the specific political forces that coalesced around each candidate, including the various stages of the Trump campaign
Global Analysis of Dynamical Decision-Making Models through Local Computation around the Hidden Saddle
Bistable dynamical switches are frequently encountered in mathematical modeling of biological systems because binary decisions are at the core of many cellular processes. Bistable switches present two stable steady-states, each of them corresponding to a distinct decision. In response to a transient signal, the system can flip back and forth between these two stable steady-states, switching between both decisions. Understanding which parameters and states affect this switch between stable states may shed light on the mechanisms underlying the decision-making process. Yet, answering such a question involves analyzing the global dynamical (i.e., transient) behavior of a nonlinear, possibly high dimensional model. In this paper, we show how a local analysis at a particular equilibrium point of bistable systems is highly relevant to understand the global properties of the switching system. The local analysis is performed at the saddle point, an often disregarded equilibrium point of bistable models but which is shown to be a key ruler of the decision-making process. Results are illustrated on three previously published models of biological switches: two models of apoptosis, the programmed cell death and one model of long-term potentiation, a phenomenon underlying synaptic plasticity
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