Universally Sloppy Parameter Sensitivities in Systems Biology

Quantitative computational models play an increasingly important role in modern biology. Such models typically involve many free parameters, and assigning their values is often a substantial obstacle to model development. Directly measuring \emph{in vivo} biochemical parameters is difficult, and collectively fitting them to other data often yields large parameter uncertainties. Nevertheless, in earlier work we showed in a growth-factor-signaling model that collective fitting could yield well-constrained predictions, even when it left individual parameters very poorly constrained. We also showed that the model had a `sloppy' spectrum of parameter sensitivities, with eigenvalues roughly evenly distributed over many decades. Here we use a collection of models from the literature to test whether such sloppy spectra are common in systems biology. Strikingly, we find that every model we examine has a sloppy spectrum of sensitivities. We also test several consequences of this sloppiness for building predictive models. In particular, sloppiness suggests that collective fits to even large amounts of ideal time-series data will often leave many parameters poorly constrained. Tests over our model collection are consistent with this suggestion. This difficulty with collective fits may seem to argue for direct parameter measurements, but sloppiness also implies that such measurements must be formidably precise and complete to usefully constrain many model predictions. We confirm this implication in our signaling model. Our results suggest that sloppy sensitivity spectra are universal in systems biology models. The prevalence of sloppiness highlights the power of collective fits and suggests that modelers should focus on predictions rather than on parameters.Comment: Submitted to PLoS Computational Biology. Supplementary Information available in "Other Formats" bundle. Discussion slightly revised to add historical contex

Dendritic cell nediated inhibition of lentiviral infection

Lentiviral entry to quiescent lymphocytes represents a 'time bomb' waiting for cellular activation to spread infection. In order to undergo immune activation T cells interact with dendritic cells presenting peptide:MHC complexes 'sampling' them to look for agonist peptides and receiving survival signals from self peptides. This makes the dendritic cell:T cell interaction an ideal checkpoint to contain lentiviral infection of quiescent lypmhocytes

Interleukins 7 and 15 Maintain Human T Cell Proliferative Capacity through STAT5 Signaling

T lymphocytes require signals from self-peptides and cytokines, most notably interleukins 7 and 15 (IL-7, IL-15), for survival. While mouse T cells die rapidly if IL-7 or IL-15 is withdrawn, human T cells can survive prolonged withdrawal of IL-7 and IL-15. Here we show that IL-7 and IL-15 are required to maintain human T cell proliferative capacity through the STAT5 signaling pathway. T cells from humanized mice proliferate better if stimulated in the presence of human IL-7 or IL-15 or if T cells are exposed to human IL-7 or IL-15 in mice. Freshly isolated T cells from human peripheral blood lose proliferative capacity if cultured for 24 hours in the absence of IL-7 or IL-15. We further show that phosphorylation of STAT5 correlates with proliferation and inhibition of STAT5 reduces proliferation. These results reveal a novel role of IL-7 and IL-15 in maintaining human T cell function, provide an explanation for T cell dysfunction in humanized mice, and have significant implications for in vitro studies with human T cells

Financial Incentives and Physician Practice Participation in Medicare’s Value‐Based Reforms

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/145327/1/hesr12743_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/145327/2/hesr12743-sup-0001-AppendixSA1.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/145327/3/hesr12743.pd

Virtual Surgical Planning in Subscapular System Free Flap Reconstruction of Midface Defects.

OBJECTIVES: Reconstruction of the midface has many inherent challenges, including orbital support, skull base reconstruction, optimizing midface projection, separation of the nasal cavity and dental rehabilitation. Subscapular system free flaps (SF) have sufficient bone stock to support complex reconstruction and the option of separate soft tissue components. This study analyzes the effect of virtual surgical planning (VSP) in SF for midface on subsite reconstruction, bone segment contact and anatomic position. MATERIALS AND METHODS: Retrospective cohort of patients with midface defects that underwent SF reconstruction at a single tertiary care institution. RESULTS: Nine cases with VSP were compared to fourteen cases without VSP. VSP was associated with a higher number of successfully reconstructed subunits (5.9 vs 4.2, 95% CI of mean difference 0.31-3.04, p = 0.018), a higher number of successful bony contact between segments (2.2 vs 1.4, 95% CI of mean difference 0.0-1.6, p = 0.050), and a higher percent of segments in anatomic position (100% vs 71%, 95% CI of mean difference 2-55%, p = 0.035). When postoperative bone position after VSP reconstruction was compared to preoperative scans, the difference in anteroposterior, vertical and lateral projection compared to the preoperative \u27ideal\u27 bone position was82% of measurements. There were no flap losses. CONCLUSION: VSP may augment SF reconstruction of the midface by allowing for improved subunit reconstruction, bony segment contact and anatomically correct bone segment positioning. VSP can be a useful adjunct for complex midface reconstruction and the benefits should be weighed against cost

On the relation between the Feynman paradox and Aharonov-Bohm effects

The magnetic Aharonov-Bohm (A-B) effect occurs when a point charge interacts with a line of magnetic flux, while its dual, the Aharonov-Casher (A-C) effect, occurs when a magnetic moment interacts with a line of charge. For the two interacting parts of these physical systems, the equations of motion are discussed in this paper. The generally accepted claim is that both parts of these systems do not accelerate, while Boyer has claimed that both parts of these systems do accelerate. Using the Euler-Lagrange equations we predict that in the case of unconstrained motion only one part of each system accelerates, while momentum remains conserved. This prediction requires a time dependent electromagnetic momentum. For our analysis of unconstrained motion the A-B effects are then examples of the Feynman paradox. In the case of constrained motion, the Euler-Lagrange equations give no forces in agreement with the generally accepted analysis. The quantum mechanical A-B and A-C phase shifts are independent of the treatment of constraint. Nevertheless, experimental testing of the above ideas and further understanding of A-B effects which is central to both quantum mechanics and electromagnetism may be possible.Comment: 21 pages, 5 figures, recently submitted to New Journal of Physic

The role of P-wave inelasticity in J/psi to pi+pi-pi0

We discuss the importance of inelasticity in the P-wave pi pi amplitude on the Dalitz distribution of 3pi events in J/psi decay. The inelasticity, which becomes sizable for pi pi masses above 1.4 GeV, is attributed to KK to pi pi rescattering. We construct an analytical model for the two-channel scattering amplitude and use it to solve the dispersion relation for the isobar amplitudes that parametrize the J/psi decay. We present comparisons between theoretical predictions for the Dalitz distribution of 3pi events with available experimental data.Comment: 10 pages, 10 figure