Effects of plasma proteins on the sieving of macromolecular tracers in the kidney

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2003.Includes bibliographical references (leaves 191-202).The ultrafiltration of plasma in the mammalian glomerulus is the first step in the processing of blood by the kidney. Proper functioning of this process is critical to the kidney's ability to effectively eliminate waste and retain desirable substances. The glomerular barrier has long been regarded as both a size and charge selective screen for plasma solutes. The origin of this selectivity is found in the unique three-layered structure of the glomerular capillary wall (GCW), consisting of a fenestrated endothelium, the interdigitating foot processes of the glomerular epithelium, and the shared glomerular basement membrane (GBM). The selectivity properties of the GCW have commonly been probed by measuring the sieving coefficients of a variety of tracers, both proteins and exogenous polymers, across the intact glomerular barrier and across isolated components of the GCW. It was found previously that the sieving coefficients of the tracers Ficoll and Ficoll sulfate across isolated GBM were greatly elevated when BSA was present at physiological levels (Bolton et al. 1998). It was suggested that most of this increase was the result of steric interactions between BSA and the tracers which increased tracer partitioning from the bulk into the GBM. Such an effect, if present, would have important implications for the interpretation of macromolecular sieving studies, both in vivo and in vitro. The goals of this thesis research were to model the effect of an abundant protein on the partitioning of a dissimilar tracer molecule, to incorporate that effect into models for glomerular sieving, and to test the partitioning model by measuring the effect of protein concentration on the partitioning of protein and Ficoll in agarose gels. The theoretical effects of solute size on partition coefficients in straight pores or randomly oriented fiber matrices have been investigated previously for very dilute solutions, where solute-solute interactions are negligible, and also for more concentrated solutions consisting of spherical solutes of uniform size. For concentrated solutions it has been found that steric and other repulsive interactions among solutes increase the partition coefficient above the dilute limit. To extend the results for porous or fibrous media to include concentrated mixtures of solutes with different sizes or shapes, we used an excluded volume approach. In this formulation, which describes steric interactions only, partition coefficients were computed by summing all volumes excluded to a solute molecule by virtue of its finite size, the finite size of other solutes, and the presence of fixed obstacles (pore walls or fibers). For a mixture of two spherical solutes, the addition of any second solute at finite concentration increased the partition coefficient of the first solute. That increase was sensitive to the size of the second solute; for a given volume fraction of the second solute, the smaller its radius, the larger the effect. When the total volume fraction of solutes was fixed, an increase in the amount of a second, smaller solute increased the partition coefficient of the first solute, whereas an increase in the amount of a second, larger solute had the opposite effect. Results were obtained also for oblate or prolate spheroidal solutes and for fibrous media with multiple fiber radii. For constant total fiber volume fraction, an increase in the amount of a second, smaller fiber decreased the partition coefficient of a spherical solute, whereas an increase in the amount of a second, larger fiber had the opposite effect. Overall, the theory suggests that the introduction of heterogeneity, whether as mixtures of solute sizes or mixtures of fiber sizes, may cause partition coefficients to differ markedly from those of uniform systems. Using the excluded volume partitioning model, the theory for the sieving of macromolecular tracers was extended to account for the presence of a second, abundant solute. Using that theory, we returned to the experimental data of Bolton et al. (1998) and attempted to model the effect of protein concentration on Ficoll sieving. The osmotic reduction in filtrate velocity caused by an abundant, mostly retained solute will also tend to elevate the tracer sieving coefficient. The osmotic effect alone explained only about one third of the observed increase in the sieving coefficients of Ficoll and Ficoll sulfate, whereas the effect of BSA on tracer partitioning was sufficient to account for the remainder. At physiological concentrations, predictions for tracer sieving in the presence of BSA were found to be insensitive to the assumed shape of the protein (sphere or prolate spheroid). The effect of plasma proteins on tracer partitioning is expected to influence sieving not only in isolated GBM, but also in intact glomerular capillaries in vivo. To test the predicted effects of solute concentration on the equilibrium partitioning of single macromolecules and macromolecule mixtures, measurements of the equilibrium partition coefficients of BSA and four narrow fractions of Ficoll were made in agarose. Solutions of each test macromolecule were equilibrated with a known volume of gel, final liquid concentrations measured, and partition coefficients calculated by applying a material balance. The partition coefficient of each molecule was measured under dilute conditions and under conditions where BSA was present at concentrated levels. All measurements were made for two different gel solid volume fractions (4 and 6%). As expected, the partition coefficients decreased with increasing gel solid volume fraction and with increasing molecular size. Increasing BSA concentration caused an increase in the partitioning of BSA itself and that of all four sizes of Ficoll. This effect was most significant for the largest molecules. A subset of the measurements repeated at a higher ionic strength demonstrated that electrostatic interactions were unimportant. The experimental results were compared with predictions generated from the excluded volume partitioning theory. Agarose was represented as a randomly oriented array of cylindrical fibers, BSA was modeled as a prolate spheroid, and Ficoll was treated as a sphere. Comparisons of the theoretical predictions with the experimental data produced generally good agreement, indicating that steric interactions among solute molecules and between solute molecules and gel fibers could explain the partitioning behavior.by Matthew Jordan Lazzara.Ph.D

Computational Analysis of the Regulation of EGFR by Protein Tyrosine Phosphatases

AbstractThe tyrosine phosphorylated epidermal growth factor receptor (EGFR) initiates numerous cell signaling pathways. Although EGFR phosphorylation levels are ultimately determined by the balance of receptor kinase and protein tyrosine phosphatase (PTP) activities, the kinetics of EGFR dephosphorylation are not well understood. Previous models of EGFR signaling have generally neglected PTP activity or computed PTP activity by considering data that do not fully reveal the kinetics and compartmentalization of EGFR dephosphorylation. We developed a compartmentalized, mechanistic model to elucidate the kinetics of EGFR dephosphorylation and the coupling of this process to phosphorylation-dependent EGFR endocytosis. Model regression against data from HeLa cells for EGFR phosphorylation response to EGFR activation, PTP inhibition, and EGFR kinase inhibition led to the conclusion that EGFR dephosphorylation occurs at the plasma membrane and in the cell interior with a timescale that is smaller than that for ligand-mediated EGFR endocytosis. The model further predicted that sufficiently rapid dephosphorylation of EGFR at the plasma membrane could potentially impede EGFR endocytosis, consistent with recent experimental findings. Overall, our results suggest that PTPs regulate multiple receptor-level phenomena via their action at the plasma membrane and cell interior and point to new possibilities for targeting PTPs for modulation of EGFR dynamics

ウィスコンシン ダイガク マディソンコウ ガ ジッシ シテイル ナンキョク ムジン キショウ カンソク (AWS) ケイカク ノ 2011-2012 ネン カキ ノ カツドウ

ウィスコンシン大学マディソン校で推進している南極無人気象観測計画(Antarctic Automatic Weather Station(AWS)program)の32 年目の観測が,2011/2012年の南半球夏期に完了した.無人気象観測網を利用して南極の気象と気候の研究が行われている.今シーズンはロス島周辺域,ロス棚氷,西南極,東南極にわたる領域で活動した.基本的に観測点のデータはアルゴス衛星を中継して配信されるが,今年はロス島周辺域の多くの観測点で,マクマード基地を中継して"Freewave modem"を通して配信された.各無人気象観測点報告には,現在設置されている測器と動作状況が含まれる.また,無人気象観測計画の全体像を,野外活動の実施状況に沿って示す.During the 2011-2012 austral summer, the Antarctic Automatic Weather Station (AWS) program at the University of Wisconsin?Madison completed its 32nd year of observations. Ongoing studies utilizing the network include topics in Antarctic meteorology and climate studies. This field season consisted of work throughout the Ross Island area, the Ross Ice Shelf, West Antarctica, and East Antarctica. Argos satellite transmissions are the primary method for relaying station data, but throughout this year, a number of stations in the Ross Island area have been converted to Freewave modems, with their data being relayed through McMurdo station. Each AWS station report contains information regarding the instrumentation currently installed and the work performed at each site. An overview of the AWS applications is included along with field work accomplished

Automatic Weather Station (AWS) Program operated by the University of Wisconsin-Madison during the 2012-2013 field season: Challenges and Successes

ウィスコンシン大学マディソン校で推進している南極無人気象観測計画（Antarctic Automatic Weather Station（AWS）program）の，2012-2013年のフィールド調査および結果の概要を報告する．今期はAWS 観測網の歴史上，特異なシーズンであった．ロス島地域が温暖であったことは氷上滑走路の利用に影響を及ぼし，いくつかの設営面での制約に直面した． 柔軟な計画により，限られた条件下でAWS サービルを最大化し，自動観測ネットワークへの要求に対応する最善の手段をとることができた．This report reviews 2012-2013 field season activities of the University of Wisconsin-Madison＇s Antarctic Automatic Weather Station (AWS) program, summarizes the science that these sites are supporting, and outlines the factors that impact the number of AWS sites serviced in any given field season. The 2012-2013 austral summer season was unusual in the AWS network history. Challenges encountered include, but are not limited to, warmer than normal conditions in the Ross Island area impacting airfield operations, changes to logistical procedures, and competition for shared resources. A flexible work plan provides the best means for taking on these challenges while maximizing AWS servicing efforts under restricted conditions and meeting the need for routine servicing that maintaining an autonomous observing network demands

Environmental Sensor Placement with Convolutional Gaussian Neural Processes

Environmental sensors are crucial for monitoring weather conditions and the impacts of climate change. However, it is challenging to maximise measurement informativeness and place sensors efficiently, particularly in remote regions like Antarctica. Probabilistic machine learning models can evaluate placement informativeness by predicting the uncertainty reduction provided by a new sensor. Gaussian process (GP) models are widely used for this purpose, but they struggle with capturing complex non-stationary behaviour and scaling to large datasets. This paper proposes using a convolutional Gaussian neural process (ConvGNP) to address these issues. A ConvGNP uses neural networks to parameterise a joint Gaussian distribution at arbitrary target locations, enabling flexibility and scalability. Using simulated surface air temperature anomaly over Antarctica as ground truth, the ConvGNP learns spatial and seasonal non-stationarities, outperforming a non-stationary GP baseline. In a simulated sensor placement experiment, the ConvGNP better predicts the performance boost obtained from new observations than GP baselines, leading to more informative sensor placements. We contrast our approach with physics-based sensor placement methods and propose future work towards an operational sensor placement recommendation system. This system could help to realise environmental digital twins that actively direct measurement sampling to improve the digital representation of reality.Comment: In review for the Climate Informatics 2023 special issue of Environmental Data Scienc

The state of the Martian climate

60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes

Winter Targeted Observing Periods during the Year of Polar Prediction in the Southern Hemisphere (YOPP-SH)

The Year of Polar Prediction in the Southern Hemisphere (YOPP-SH) held seven targeted observing periods (TOPs) during the 2022 austral winter to enhance atmospheric predictability over the Southern Ocean and Antarctica. The TOPs of 5–10-day duration each featured the release of additional radiosonde balloons, more than doubling the routine sounding program at the 24 participating stations run by 14 nations, together with process-oriented observations at selected sites. These extra sounding data are evaluated for their impact on forecast skill via data denial experiments with the goal of refining the observing system to improve numerical weather prediction for winter conditions. Extensive observations focusing on clouds and precipitation primarily during atmospheric river (AR) events are being applied to refine model microphysical parameterizations for the ubiquitous mixed-phase clouds that frequently impact coastal Antarctica. Process studies are being facilitated by high-time-resolution series of observations and forecast model output via the YOPP Model Intercomparison and Improvement Project (YOPPsiteMIIP). Parallel investigations are broadening the scope and impact of the YOPP-SH winter TOPs. Studies of the Antarctic tourist industry’s use of weather services show the scope for much greater awareness of the availability of forecast products and the skill they exhibit. The Sea Ice Prediction Network South (SIPN South) analysis of predictions of the sea ice growth period reveals that the forecast skill is superior to the sea ice retreat phase

The Year of Polar Prediction in the Southern Hemisphere (YOPP-SH)

The Year of Polar Prediction in the Southern Hemisphere (YOPP-SH) had a Special Observing Period (SOP) that ran from November 16, 2018 to February 15, 2019, a period chosen to span the austral warm season months of greatest operational activity in the Antarctic. Some 2200 additional radiosondes were launched during the 3-month SOP, roughly doubling the routine program, and the network of drifting buoys in the Southern Ocean was enhanced. An evaluation of global model forecasts during the SOP and using its data has confirmed that extratropical Southern Hemisphere forecast skill lags behind that in the Northern Hemisphere with the contrast being greatest between the southern and northern polar regions. Reflecting the application of the SOP data, early results from observing system experiments show that the additional radiosondes

Quantitative modeling perspectives on the ErbB system of cell regulatory processes

The complexities of the processes involved in ErbB-mediated regulation of cellular phenotype are broadly appreciated, so much so that it might be reasonably argued that this highly studied system provided significant impetus for the systems perspective on cell signaling processes in general. Recent years have seen major advances in the level of characterization of the ErbB system as well as our ability to make measurements of the system. This new data provides significant new insight, while at the same time creating new challenges for making quantitative statements and predictions with certainty. Here, we discuss recent advances in each of these directions and the interplay between them, with a particular focus on quantitative modeling approaches to interpret data and provide predictive power. Our discussion follows the sequential order of ErbB pathway activation, beginning with considerations of receptor/ligand interactions and dynamics, proceeding to the generation of intracellular signals, and ending with determination of cellular phenotype. As discussed herein, these processes become increasingly difficult to describe or interpret in terms of traditional models, and we review emerging methodologies to address this complexity.National Cancer Institute (U.S.). Integrative Cancer Biology Program (U54-CA112967)National Cancer Institute (U.S.) (R01-CA096504