On the Helix-coil Transition in Alanine-based Polypeptides in Gas Phase

Using multicanonical simulations, the authors study the effect of charged end groups on helix formation in alanine based polypeptides. They confirm earlier reports that neutral polyalanine exhibits a pronounced helix-coil transition in gas phase simulations. Introducing a charged Lys+ at the C terminal stabilizes the helix and leads to a higher transition temperature. On the other hand, adding the Lys+ at the N terminal inhibits helix formation. Instead, a more globular structure was found. These results are in agreement with recent experiments on alanine based polypeptides in gas phase. They indicate that present force fields describe accurately the intramolecular interactions in proteins

Side chain and backbone ordering in a polypeptide

We report results from multicanonical simulations of polyglutamic acid chains of length of ten residues. For this simple polypeptide we observe a decoupling of backbone and side-chain ordering in the folding process. While the details of the two transitions vary between the peptide in gas phase and in an implicit solvent, our results indicate that, independent of the specific surroundings, upon continuously lowering the temperature side-chain ordering occurs only after the backbone topology is completely formed

Ions in Fluctuating Channels: Transistors Alive

Ion channels are proteins with a hole down the middle embedded in cell membranes. Membranes form insulating structures and the channels through them allow and control the movement of charged particles, spherical ions, mostly Na+, K+, Ca++, and Cl-. Membranes contain hundreds or thousands of types of channels, fluctuating between open conducting, and closed insulating states. Channels control an enormous range of biological function by opening and closing in response to specific stimuli using mechanisms that are not yet understood in physical language. Open channels conduct current of charged particles following laws of Brownian movement of charged spheres rather like the laws of electrodiffusion of quasi-particles in semiconductors. Open channels select between similar ions using a combination of electrostatic and 'crowded charge' (Lennard-Jones) forces. The specific location of atoms and the exact atomic structure of the channel protein seems much less important than certain properties of the structure, namely the volume accessible to ions and the effective density of fixed and polarization charge. There is no sign of other chemical effects like delocalization of electron orbitals between ions and the channel protein. Channels play a role in biology as important as transistors in computers, and they use rather similar physics to perform part of that role. Understanding their fluctuations awaits physical insight into the source of the variance and mathematical analysis of the coupling of the fluctuations to the other components and forces of the system.Comment: Revised version of earlier submission, as invited, refereed, and published by journa

A categorification of Morelli's theorem

We prove a theorem relating torus-equivariant coherent sheaves on toric varieties to polyhedrally-constructible sheaves on a vector space. At the level of K-theory, the theorem recovers Morelli's description of the K-theory of a smooth projective toric variety. Specifically, let $X$ be a proper toric variety of dimension $n$ and let M_\bR = \mathrm{Lie}(T_\bR^\vee)\cong \bR^n be the Lie algebra of the compact dual (real) torus T_\bR^\vee\cong U(1)^n. Then there is a corresponding conical Lagrangian \Lambda \subset T^*M_\bR and an equivalence of triangulated dg categories \Perf_T(X) \cong \Sh_{cc}(M_\bR;\Lambda), where \Perf_T(X) is the triangulated dg category of perfect complexes of torus-equivariant coherent sheaves on $X$ and \Sh_{cc}(M_\bR;\Lambda) is the triangulated dg category of complex of sheaves on M_\bR with compactly supported, constructible cohomology whose singular support lies in $\Lambda$. This equivalence is monoidal---it intertwines the tensor product of coherent sheaves on $X$ with the convolution product of constructible sheaves on M_\bR.Comment: 20 pages. This is a strengthened version of the first half of arXiv:0811.1228v3, with new results; the second half becomes arXiv:0811.1228v

Monte Carlo Methods for Rough Free Energy Landscapes: Population Annealing and Parallel Tempering

Parallel tempering and population annealing are both effective methods for simulating equilibrium systems with rough free energy landscapes. Parallel tempering, also known as replica exchange Monte Carlo, is a Markov chain Monte Carlo method while population annealing is a sequential Monte Carlo method. Both methods overcome the exponential slowing associated with high free energy barriers. The convergence properties and efficiency of the two methods are compared. For large systems, population annealing initially converges to equilibrium more rapidly than parallel tempering for the same amount of computational work. However, parallel tempering converges exponentially and population annealing inversely in the computational work so that ultimately parallel tempering approaches equilibrium more rapidly than population annealing.Comment: 10 pages, 3 figure

Benefits of biomarker selection and clinico-pathological covariate inclusion in breast cancer prognostic models

Introduction: Multi-marker molecular assays have impacted management of early stage breast cancer, facilitating adjuvant chemotherapy decisions. We generated prognostic models that incorporate protein-based molecular markers and clinico-pathological variables to improve survival prediction. Methods: We used a quantitative immunofluorescence method to study protein expression of 14 markers included in the Oncotype DX™ assay on a 638 breast cancer patient cohort with 15-year follow-up. We performed cross-validation analyses to assess performance of multivariate Cox models consisting of these markers and standard clinico-pathological covariates, using an average time-dependent Area Under the Receiver Operating Characteristic curves and compared it to nested Cox models obtained by robust backward selection procedures. Results: A prognostic index derived from of a multivariate Cox regression model incorporating molecular and clinico-pathological covariates (nodal status, tumor size, nuclear grade, and age) is superior to models based on molecular studies alone or clinico-pathological covariates alone. Performance of this composite model can be further improved using feature selection techniques to prune variables. When stratifying patients by Nottingham Prognostic Index (NPI), the most prognostic markers in high and low NPI groups differed. Similarly, for the node-negative, hormone receptor-positive sub-population, we derived a compact model with three clinico-pathological variables and two protein markers that was superior to the full model. Conclusions: Prognostic models that include both molecular and clinico-pathological covariates can be more accurate than models based on either set of features alone. Furthermore, feature selection can decrease the number of molecular variables needed to predict outcome, potentially resulting in less expensive assays.This work was supported by a grant from the Susan G Komen Foundation (to YK)

Role of the 12-lipoxygenase pathway in diabetes pathogenesis and complications

12-lipoxygenase (12-LOX) is one of several enzyme isoforms responsible for the metabolism of arachidonic acid and other poly-unsaturated fatty acids to both pro- and anti-inflammatory lipid mediators. Mounting evidence has shown that 12-LOX plays a critical role in the modulation of inflammation at multiple checkpoints during diabetes development. Due to this, interventions to limit pro-inflammatory 12-LOX metabolites either by isoform-specific 12-LOX inhibition, or by providing specific fatty acid substrates via dietary intervention, has the potential to significantly and positively impact health outcomes of patients living with both type 1 and type 2 diabetes. To date, the development of truly specific and efficacious inhibitors has been hampered by homology of LOX family members; however, improvements in high throughput screening have improved the inhibitor landscape. Here, we describe the function and role of human 12-LOX, and mouse 12-LOX and 12/15-LOX, in the development of diabetes and diabetes-related complications, and describe promise in the development of strategies to limit pro-inflammatory metabolites, primarily via new small molecule 12-LOX inhibitors

Gold nanorods as a contrast agent for Doppler optical coherence tomography

Purpose: To investigate gold nanorods (GNRs) as a contrast agent to enhance Doppler optical coherence tomography (OCT) imaging of the intrascleral aqueous humor outflow. Methods: A serial dilution of GNRs was scanned with a spectral-domain OCT device (Bioptigen, Durham, NC) to visualize Doppler signal. Doppler measurements using GNRs were validated using a controlled flow system. To demonstrate an application of GNR enhanced Doppler, porcine eyes were perfused at constant pressure with mock aqueous alone or 1.0×10 12 GNR/mL mixed with mock aqueous. Twelve Doppler and volumetric SD-OCT scans were obtained from the limbus in a radial fashion incremented by 30°, forming a circular scan pattern. Volumetric flow was computed by integrating flow inside non-connected vessels throughout all 12 scans around the limbus. Results: At the GNR concentration of 0.7×1012 GNRs/mL, Doppler signal was present through the entire depth of the testing tube without substantial attenuation. A well-defined laminar flow profile was observed for Doppler images of GNRs flowing through the glass capillary tube. The Doppler OCT measured flow profile was not statistically different from the expected flow profile based upon an autoregressive moving average model, with an error of -0.025 to 0.037 mm/s (p = 0.6435). Cross-sectional slices demonstrated the ability to view anterior chamber outflow ex-vivo using GNR-enhanced Doppler OCT. Doppler volumetric flow measurements were comparable to flow recorded by the perfusion system. Conclusions: GNRs created a measureable Doppler signal within otherwise silent flow fields in OCT Doppler scans. Practical application of this technique was confirmed in a constant pressure ex-vivo aqueous humor outflow model in porcine eyes. © 2014 Wang et al

Coarse-grained dynamics of an activity bump in a neural field model

We study a stochastic nonlocal PDE, arising in the context of modelling spatially distributed neural activity, which is capable of sustaining stationary and moving spatially-localized ``activity bumps''. This system is known to undergo a pitchfork bifurcation in bump speed as a parameter (the strength of adaptation) is changed; yet increasing the noise intensity effectively slowed the motion of the bump. Here we revisit the system from the point of view of describing the high-dimensional stochastic dynamics in terms of the effective dynamics of a single scalar "coarse" variable. We show that such a reduced description in the form of an effective Langevin equation characterized by a double-well potential is quantitatively successful. The effective potential can be extracted using short, appropriately-initialized bursts of direct simulation. We demonstrate this approach in terms of (a) an experience-based "intelligent" choice of the coarse observable and (b) an observable obtained through data-mining direct simulation results, using a diffusion map approach.Comment: Corrected aknowledgement

A beginner's introduction to Fukaya categories

The goal of these notes is to give a short introduction to Fukaya categories and some of their applications. The first half of the text is devoted to a brief review of Lagrangian Floer (co)homology and product structures. Then we introduce the Fukaya category (informally and without a lot of the necessary technical detail), and briefly discuss algebraic concepts such as exact triangles and generators. Finally, we mention wrapped Fukaya categories and outline a few applications to symplectic topology, mirror symmetry and low-dimensional topology. This text is based on a series of lectures given at a Summer School on Contact and Symplectic Topology at Universit\'e de Nantes in June 2011.Comment: 42 pages, 13 figure