Binding of malaria T cell epitopes to DR and DQ molecules in vitro correlates with immunogenicity in vivo: identification of a universal T cell epitope in the Plasmodium falciparum circumsporozoite protein

The efficacy of a malaria peptide vaccine would be enhanced by the inclusion of a parasite-derived universal T cell epitope to ensure that all vaccinees develop parasite-specific cellular and humoral immunity. Two circumsporozoite (CS) protein T cell epitopes, previously identified by CD4+ T cell clones derived from Plasmodium falciparum sporozoite-immunized volunteers, were studied to determine their HLA class II binding potential. One epitope, located in amino acid (aa) 326-345 of the P. falciparum (NF54 strain) CS protein, was "universal" in that it could bind to multiple DR and DQ molecules in vitro. In contrast, the second epitope, T1, which is located in the CS repeat region, was recognized by T cells in the context of DQ6 (DQB1*0603) and did not bind with high affinity to any of the class II molecules tested in the peptide binding assays. The in vitro patterns of peptide/HLA interactions correlated with immunogenicity in vivo. A multiple antigen peptide (MAP) containing the aa 326-345 epitope elicited responses in eight inbred strains (H-2(a,b,d,k,p,q,r,s)), while the T1 MAP was recognized by only a single haplotype, H-2b. The combination of the universal aa 326-345 T cell epitope and the T1 repeat in a di-epitope MAP overcame the genetic restriction to the P. falciparum CS repeat region and elicited antisporozoite Ab responses in all of the MAP-immunized mice. Synthetic peptide malaria vaccines containing the aa 326-345 universal T cell epitope would be expected to elicit parasite-specific immune responses in both sporozoite-primed and naive individuals of diverse genetic backgrounds.     

Tackling heterogeneous concept drift with the Self-Adjusting Memory (SAM)

Instance matching is the problem of determining whether two instances describe the same real-world entity or not. Instance matching plays a key role in data integration and data cleansing, especially for building a knowledge base. For example, we can regard each article in encyclopedias as an instance, and a group of articles which refers to the same real-world object as an entity. Therefore, articles about Washington should be distinguished and grouped into different entities such as Washington, D.C (the capital of the USA), George Washington (first president of the USA), Washington (a state of the USA), Washington (a village in West Sussex, England), Washington F.C. (a football club based in Washington, Tyne and Wear, England), Washington, D.C. (a novel). In this paper, we proposed a novel instance matching approach Active Instance Matching with Pairwise Constraints, which can bring the human into the loop of instance matching. The proposed approach can generate candidate pairs in advance to reduce the computational complexity, and then iteratively select the most informative pairs according to the uncertainty, influence, connectivity and diversity of pairs. We evaluated our approach one two publicly available datasets AMINER and WIDE-NUS and then applied our approach to the two large-scale real-world datasets, Baidu Baike and Hudong Baike, to build a Chinese knowledge base. The experiments and practice illustrate the effectiveness of our approach.     

Parameter estimation in abruptly changing dynamic environments using stochastic learning weak estimator

Many real-life dynamical systems experience abrupt changes followed by almost stationary periods. In this paper, we consider streams of data exhibiting such abrupt behavior and investigate the problem of tracking their statistical properties in an online manner. Wedevise a tracking procedure where an estimator that is suitable for a stationary environment is combined together with an estimator suitable for a dynamic environment. The current estimate is based on the stationary estimator unless a statistically significant difference is observed between both estimators. The stationary estimate is deemed off track and a large update (jump) is given to get the stationary estimate back on track. We use the Stochastic Learning Weak Estimator (SLWE) as the dynamic estimator. The SLWE is known to be the state-of-the art solution to tracking the properties of non-stationary environments, due to its multiplicative update form. Therefore, the SLWE is a better choice to accompany a stationary estimator than the far more common sliding window based approach. A theoretically well founded statistical testing procedure is developed to detect a significant difference between the stationary and dynamical estimators. Although our procedure bears similarities to the event detection procedure suggested by Ross et al. (Pattern Recogn Lett, 33(2):191–198, 2012), it is rather well founded theoretically. First, Ross et al. ignore the uncertainty in the stationary estimator in the detection procedure. Second, the detection threshold is determined based on heuristics and therefore lacks a solid statistical foundation. Extensive simulation results, based on both synthetic and real-life data related to news topic classification, demonstrate that our estimation procedure is easy to tune and outperforms legacy works.     

Spatial,seasonal, and topographical patterns of surface albedo in Norwegian forests and cropland

Land surface albedo is a key parameter of the Earth’s climate system. It has high variability in space, time, and land cover and it is among the most important variables in climate models. Extensive large-scale estimates can help model calibration and improvement to reduce uncertainties in quantifying the influence of surface albedo changes on the planetary radiation balance. Here, we use satellite retrievals of Moderate Resolution Imaging Spectroradiometer (MODIS) surface albedo (MCD43A3), high-resolution land-cover maps, and meteorological records to characterize climatological albedo variations in Norway across latitude, seasons, land-cover type (deciduous forests, coniferous forests, and cropland), and topography. We also investigate the net changes in surface albedo and surface air temperature through site pair analysis to mimic the effects of land-use transitions between forests and cropland and among different tree species. We find that surface albedo increases at increasing latitude in the snow season, and cropland and deciduous forests generally have higher albedo values than coniferous forests, but for few days in spring. Topography has a large influence on MODIS albedo retrievals, with values that can change up to 100% for the same land-cover class (e.g. spruce in winter) under varying slopes and aspect of the terrain. Cropland sites have surface air temperature higher than adjacent forested sites, and deciduous forests are slightly colder than adjacent coniferous forests. By integrating satellite measurements and high-resolution vegetation maps, our results provide a large semi-empirical basis that can assist future studies to better predict changes in a fundamental climate-regulating service such as surface albedo.     

Controlling Cellular Uptake and Toxicity of Polyphenylene Dendrimers by Chemical Functionalization

Polyphenylene dendrimers (PPDs) represent a unique class of macromolecules based on their monodisperse and shape‐persistent nature. These characteristics have enabled the synthesis of a new genre of “patched” surface dendrimers, where their exterior can be functionalized with a variety of polar and nonpolar substituents to yield lipophilic binding sites in a site‐specific way. Although such materials are capable of complexing biologically relevant molecules, show high cellular uptake in various cell lines, and low to no toxicity, there is minimal understanding of the driving forces to these characteristics. We investigated whether it is the specific chemical functionalities, relative quantities of each moiety, or the “patched” surface patterning on the dendrimers that more significantly influences their behavior in biological media.     

Integrin-mediated signalling through the MAP-kinase pathway

The mitogen activated protein (MAP) kinase cascade, leading to extracellular-regulated kinase (ERK) activation, is a key regulator of cell growth and proliferation. The effects of ERK are mediated by differences in ERK signalling dynamics, including magnitude and duration. In vivo, ERK signalling is stimulated by both growth factors and adhesion signals. A model for adhesion-mediated ERK activation is presented. Outputs of the model such as ERK and FAK activation, as well as responses to different ligand densities, are compared with published experimental data. The model then serves as a basis for understanding how adhesion may contribute to ERK signalling through changes in the dynamics of focal adhesion kinase activation. The main parameters influencing ERK are determined through screening analyses and parameter variation. With these parameters, key points in the pathway that give rise to changes in downstream signalling dynamics are identified. In particular, oncogenic Raf and Ras promote cell growth by increasing the magnitude and duration, respectively, of ERK activity.     

Mathematical model for the hemodynamic response to venous occlusion measured with near-infrared spectroscopy in the human forearm

We propose a mathematical model to describe the hemodynamic changes induced by a venous occlusion in a human limb. These hemodynamic changes, which include an increase in blood volume, a reduction in blood flow, and modifications to the oxygen saturation of hemoglobin, can all be measured noninvasively with near-infrared spectroscopy (NIRS). To test the model, we have performed NIRS measurements on the human forearm, specifically on the brachioradialis muscle, during venous occlusion induced by a pneumatic cuff inflated around the upper arm to pressures within the range 10-60 mmHg. We have found a good agreement between parameters measured by NIRS (total hemoglobin concentration and hemoglobin saturation) and the corresponding model parameters (capacitor voltage and arterial/capillary branch current). In particular, model and experiment indicate that the time constant for blood accumulation during venous occlusion (approximately 73-79 s) is much slower than the time constant for blood drainage following cuff release (approximately 5 s). These results indicate that this mathematical model can be a valuable analytical tool to characterize, optimize, and further develop diagnostic measurement schemes that use venous occlusion approaches.     

Compact multimodal adaptive-optics spectral-domain optical coherence tomography instrument for retinal imaging

We have developed a compact, multimodal instrument for simultaneous acquisition of en face quasi-confocal fundus images and adaptive-optics (AO) spectral-domain optical coherence tomography (SDOCT) cross-sectional images. The optical system including all AO and SDOCT components occupies a 60x60 cm breadboard that can be readily transported for clinical applications. The AO component combines a Hartmann-Shack wavefront sensor and a microelectromechanical systems-based deformable mirror to sense and correct ocular aberrations at 15 Hz with a maximum stroke of 4 microm. A broadband superluminescent diode source provides 4 mum depth resolution for SDOCT imaging. In human volunteer testing, we observed up to an 8 dB increase in OCT signal and a corresponding lateral resolution of <10 microm as a result of AO correction.     

Optimal laminate design subject to single membrane loads

In this paper we investigate optimization of laminates for maximal membrane stiffness under single in-plane loads. The design parameters are the relative ply thicknesses and fiber orientations of an arbitrary number of plies. The design is allowed to vary in a pointwise fashion throughout the structure.From prior work on lamination parameters (Hammeret al. 1997), it is known that the optimal design is given by either some sort of two ply lay-up in special strain situations or otherwise by just a single rotated ply. This is exploited in the present analysis to derive analytically the unique parameters of the optimal design (cross-ply, angle-ply or single ply) as expressions of the membrane forces. Both high and low shear stiffness material are treated. Furthermore the analysis covers all possible local strain or membrane force situations.Finally, it is shown how these expressions for the optimal configuration of the laminate also appear as bounds on the principal membrane forces in order to obtain alignment between the numerically largest principal membrane force and principal strain.     

Distribution of Organic Carbon in the Berkeley Pit Lake, Butte, Montana

Abstract.  The concentration of dissolved organic carbon (DOC) in the Berkeley pit lake water ranges from 2 to 4 mg/L, and is comparable to that of its inflow waters. On the dates sampled, the DOC concentrations decreased towards the surface of the lake, in a manner similar to the concentration of dissolved Fe. This may reflect adsorption of DOC onto newly formed ferric precipitates in the epilimnion of the lake. The total organic carbon (TOC) content of the lake sediment is 0.20 to 0.33%, and is on the low end of TOC in natural aquatic sediments. In contrast, the DOC concentrations of sediment pore waters are unusually high, ranging from 50 to 380 mg/L, and are much higher than DOC values of pore waters from typical marine or lacustrine sediments. The high DOC concentrations are explained by release of adsorbed organic carbon from ferric precipitates as they age and recrystallize, coupled with the relative scarcity of heterotrophic bacteria in the acidic and heavy metal-rich waters that would otherwise consume DOC through reduction of sulfate.