Advancing multiple model-based control of complex biological systems: Applications in T cell biology

Activated CD4+ T cells are important regulators of the adaptive immune response against invading pathogens and cancerous host cells. The process of activation is mediated by the T cell receptor and a vast network of intracellular signal transduction pathways, which recognize and interpret antigenic signals to determine the cell\u27s response. The critical role of these early signaling events in normal cell function and the pathogenesis of disease ultimately make them attractive therapeutic targets for numerous autoimmune diseases and cancers. Scientists increasingly rely on predictive mathematical models and control-theoretic tools to design effective strategies to manipulate cellular processes for the advancement of knowledge or therapeutic gain. However, the application of modern control theory to intracellular signal transduction is complicated by a unique set of intrinsic properties and technical limitations. These include complexities in the signaling network such as crosstalk, feedback and nonlinearity, and a dearth of rapid quantitative measurement techniques and specific and orthogonal modulators, the major consequences of which are uncertainty in the model representation and the prevention of real-time measurement feedback. Integrating such uncertainties and limitations into a control-theoretic approach under practical constraints represents an open challenge in controller design. The work presented in this dissertation addresses these challenges through the development of a computational methodology to aid in the design of experimental strategies to predictably manipulate intracellular signaling during the process of CD4+ T cell activation. This work achieves two main objectives: (1) the development of a generalized control-theoretic tool to effectively control uncertain nonlinear systems in the absence of real-time measurement feedback, and (2) the development and calibration of a predictive mathematical model (or collection of models) of CD4+ T cell activation to help derive experimental inputs to robustly force the system dynamics along prescribed trajectories. The crux of this strategy is the use of multiple data-supported models to inform the controller design. These models may represent alternative hypotheses for signaling mechanisms and give rise to distinct network topologies or kinetic rate scenarios and yet remain consistent with available data. Here, a novel adaptive weighting algorithm predicts variations in the models\u27 predictive accuracy over the admissible input space to produce a more reliable compromise solution from multiple competing objectives, a result corroborated by several experimental studies. This dissertation provides a practical means to effectively utilize the collective predictive capacity of multiple prediction models to predictably and robustly direct CD4 + T cells to exhibit regulatory, helper and anergic T cell-like signaling profiles through pharmacological manipulations in the absence of measurement feedback. The framework and procedures developed herein are expected to widely applicable to a more general class of continuous dynamical systems for which real-time feedback is not readily available. Furthermore, the ability to predictably and precisely control biological systems could greatly advance how we study and interrogate such systems and aid in the development of novel therapeutic designs for the treatment of disease

Heterogeneity in Short Gamma-ray Bursts

We analyze the Swift/BAT sample of short gamma-ray bursts, using an objective Bayesian Block procedure to extract temporal descriptors of the bursts' initial pulse complexes (IPCs). The sample comprises 12 and 41 bursts with and without extended emission (EE) components, respectively. IPCs of non-EE bursts are dominated by single pulse structures, while EE bursts tend to have two or more pulse structures. The medians of characteristic timescales - durations, pulse structure widths, and peak intervals - for EE bursts are factors of ~ 2-3 longer than for non-EE bursts. A trend previously reported by Hakkila and colleagues unifying long and short bursts - the anti-correlation of pulse intensity and width - continues in the two short burst groups, with non-EE bursts extending to more intense, narrower pulses. In addition we find that preceding and succeeding pulse intensities are anti-correlated with pulse interval. We also examine the short burst X-ray afterglows as observed by the Swift/XRT. The median flux of the initial XRT detections for EE bursts (~ 6 x 10^-10 erg cm^-2 s^-1) is ~> 20 x brighter than for non-EE bursts, and the median X-ray afterglow duration for EE bursts (~ 60,000 s) is ~ 30 x longer than for non-EE bursts. The tendency for EE bursts toward longer prompt-emission timescales and higher initial X-ray afterglow fluxes implies larger energy injections powering the afterglows. The longer-lasting X-ray afterglows of EE bursts may suggest that a significant fraction explode into more dense environments than non-EE bursts, or that the sometimes-dominant EE component efficiently powers the afterglow. Combined, these results favor different progenitors for EE and non-EE short bursts.Comment: 30 pages, 11 figures, 3 tables; accepted to The Astrophysical Journa

PTF10iya: A short-lived, luminous flare from the nuclear region of a star-forming galaxy

We present the discovery and characterisation of PTF10iya, a short-lived (dt ~ 10 d, with an optical decay rate of ~ 0.3 mag per d), luminous (M_g ~ -21 mag) transient source found by the Palomar Transient Factory. The ultraviolet/optical spectral energy distribution is reasonably well fit by a blackbody with T ~ 1-2 x 10^4 K and peak bolometric luminosity L_BB ~ 1-5 x 10^44 erg per s (depending on the details of the extinction correction). A comparable amount of energy is radiated in the X-ray band that appears to result from a distinct physical process. The location of PTF10iya is consistent with the nucleus of a star-forming galaxy (z = 0.22405 +/- 0.00006) to within 350 mas (99.7 per cent confidence radius), or a projected distance of less than 1.2 kpc. At first glance, these properties appear reminiscent of the characteristic "big blue bump" seen in the near-ultraviolet spectra of many active galactic nuclei (AGNs). However, emission-line diagnostics of the host galaxy, along with a historical light curve extending back to 2007, show no evidence for AGN-like activity. We therefore consider whether the tidal disruption of a star by an otherwise quiescent supermassive black hole may account for our observations. Though with limited temporal information, PTF10iya appears broadly consistent with the predictions for the early "super-Eddington" phase of a solar-type star disrupted by a ~ 10^7 M_sun black hole. Regardless of the precise physical origin of the accreting material, the large luminosity and short duration suggest that otherwise quiescent galaxies can transition extremely rapidly to radiate near the Eddington limit; many such outbursts may have been missed by previous surveys lacking sufficient cadence.Comment: 18 pages, 8 figures; revised following referee's comment

Bone Marrow-Derived Progenitor Cells Augment Venous Remodeling in a Mouse Dorsal Skinfold Chamber Model

The delivery of bone marrow-derived cells (BMDCs) has been widely used to stimulate angiogenesis and arteriogenesis. We identified a progenitor-enriched subpopulation of BMDCs that is able to augment venular remodeling, a generally unexplored area in microvascular research. Two populations of BMDCs, whole bone marrow (WBM) and Lin−/Sca-1+ progenitor cells, were encapsulated in sodium alginate and delivered to a mouse dorsal skinfold chamber model. Upon observation that encapsulated Sca-1+ progenitor cells enhance venular remodeling, the cells and tissue were analyzed on structural and molecular levels. Venule walls were thickened and contained more nuclei after Sca-1+ progenitor cell delivery. In addition, progenitors expressed mRNA transcript levels of chemokine (C-X-C motif) ligand 2 (CXCL2) and interferon gamma (IFNγ) that are over 5-fold higher compared to WBM. Tissues that received progenitors expressed significantly higher protein levels of vascular endothelial growth factor (VEGF), monocyte chemotactic protein-1 (MCP-1), and platelet derived growth factor-BB (PDGF-BB) compared to tissues that received an alginate control construct. Nine days following cell delivery, tissue from progenitor recipients contained 39% more CD45+ leukocytes, suggesting that these cells may enhance venular remodeling through the modulation of the local immune environment. Results show that different BMDC populations elicit different microvascular responses. In this model, Sca-1+ progenitor cell-derived CXCL2 and IFNγ may mediate venule enlargement via modulation of the local inflammatory environment

Spectra of Hydrogen-poor Superluminous Supernovae from the Palomar Transient Factory

Most Type I superluminous supernovae (SLSNe-I) reported to date have been identified by their high peak luminosities and spectra lacking obvious signs of hydrogen. We demonstrate that these events can be distinguished from normal-luminosity SNe (including Type Ic events) solely from their spectra over a wide range of light-curve phases. We use this distinction to select 19 SLSNe-I and four possible SLSNe-I from the Palomar Transient Factory archive (including seven previously published objects). We present 127 new spectra of these objects and combine these with 39 previously published spectra, and we use these to discuss the average spectral properties of SLSNe-I at different spectral phases. We find that Mn II most probably contributes to the ultraviolet spectral features after maximum light, and we give a detailed study of the O II features that often characterize the early-time optical spectra of SLSNe-I. We discuss the velocity distribution of O II, finding that for some SLSNe-I this can be confined to a narrow range compared to relatively large systematic velocity shifts. Mg II and Fe II favor higher velocities than O II and C II, and we briefly discuss how this may constrain power-source models. We tentatively group objects by how well they match either SN 2011ke or PTF12dam and discuss the possibility that physically distinct events may have been previously grouped together under the SLSN-I label

Kilonova Luminosity Function Constraints Based on Zwicky Transient Facility Searches for 13 Neutron Star Merger Triggers during O3

We present a systematic search for optical counterparts to 13 gravitational wave (GW) triggers involving at least one neutron star during LIGO/Virgo's third observing run (O3). We searched binary neutron star (BNS) and neutron star black hole (NSBH) merger localizations with the Zwicky Transient Facility (ZTF) and undertook follow-up with the Global Relay of Observatories Watching Transients Happen (GROWTH) collaboration. The GW triggers had a median localization area of 4480 deg², a median distance of 267 Mpc, and false-alarm rates ranging from 1.5 to 10⁻²⁵ yr⁻¹. The ZTF coverage in the g and r bands had a median enclosed probability of 39%, median depth of 20.8 mag, and median time lag between merger and the start of observations of 1.5 hr. The O3 follow-up by the GROWTH team comprised 340 UltraViolet/Optical/InfraRed (UVOIR) photometric points, 64 OIR spectra, and three radio images using 17 different telescopes. We find no promising kilonovae (radioactivity-powered counterparts), and we show how to convert the upper limits to constrain the underlying kilonova luminosity function. Initially, we assume that all GW triggers are bona fide astrophysical events regardless of false-alarm rate and that kilonovae accompanying BNS and NSBH mergers are drawn from a common population; later, we relax these assumptions. Assuming that all kilonovae are at least as luminous as the discovery magnitude of GW170817 (−16.1 mag), we calculate that our joint probability of detecting zero kilonovae is only 4.2%. If we assume that all kilonovae are brighter than −16.6 mag (the extrapolated peak magnitude of GW170817) and fade at a rate of 1 mag day⁻¹ (similar to GW170817), the joint probability of zero detections is 7%. If we separate the NSBH and BNS populations based on the online classifications, the joint probability of zero detections, assuming all kilonovae are brighter than −16.6 mag, is 9.7% for NSBH and 7.9% for BNS mergers. Moreover, no more than 10⁻⁴, or φ > 30° to be consistent with our limits. We look forward to searches in the fourth GW observing run; even 17 neutron star mergers with only 50% coverage to a depth of −16 mag would constrain the maximum fraction of bright kilonovae to <25%

Enhanced Protein Expression of VEGF, MCP-1, and PDGF-BB in Dorsal Skinfold Chambers.

<p>(A) Delivery of encapsulated Sca-1⁺ progenitor cells elevated VEGF protein expression in dorsal tissue at day 4. (B) Delivery of encapsulated Sca-1⁺ progenitor cells elevated MCP-1 protein expression in dorsal tissue at day 4. (C) Delivery of encapsulated Sca-1⁺ progenitor cells elevated PDGF-BB protein expression in dorsal tissue at day 4. * indicates p<0.05 as calculated by ANOVA. Data are means +/− S.E.</p

Comparison of Negative Threshold to Cycle Number of Gene Amplification for WBM and Sca-1⁺ Progenitors.

<p>Fn-1, IFN γ, and CXCL2 amplify at cycles significantly below the negative threshold in both WBM and Sca-1⁺ progenitors, while FGF-2 amplifies at a cycle number indicative of low genetic expression in both cell types. * indicates p<0.05 as calculated by ANOVA. Data are means +/− S.E.</p

Inflammatory Cell Recruitment in Sca-1⁺ Progenitor Cell Recipients and Control Animals.

<p>(A) Number of CD45 positive cells per square micron skinfold chamber tissue. (B) Total percentage of CD45 expressing cells in the skinfold chamber tissue. * indicates p<0.05 as calculated by ANOVA. Data are means +/− S.E.</p