Bayesian Network Approaches for Refining and Expanding Cellular and Immunological Pathways.

This thesis focuses on computational analysis of cellular and immune pathways of living cells in response to molecular signals using Bayesian networks (BN). Although Bayesian networks have been applied to the reconstruction and expansion of gene regulatory and protein signaling pathways using existing biological data, the results generated from existing BN methods show high false positive and false negative rates. To resolve these issues, two major Bayesian network approaches were developed to allow refinement and expansion of known biological pathways to identify new interactions and molecular entities participating in the pathway. How to refine existing Bayesian networks to identify the best-supported interactions predicted using underlying biological data was explored initially. A posterior probability-based EdgeClipper refinement algorithm was developed to identify well-supported interaction hypotheses in distributions of saved BNs. EdgeClipper incorporates posterior weighting to prioritize and clip interactions. This approach identified many known interactions in synthetic and Escherichia coli reactive oxygen species (ROS) pathways as well as novel interactions and improved specificity with decreasing sensitivity. Second, an expansion approach called BN+1 was introduced to identify unknown though potentially novel pathway members which likely influence biological pathways. BN+1 was applied to the expansion of several synthetic, prokaryotic, and eukaryotic pathways. Major findings included the identification of genetic interactions between genes gadX and uspE and their direct regulation of biofilm activities in E.coli, which was verified experimentally. Finally, the expansion and refinement algorithms were combined to recover a known acid fitness island and new putative acid fitness regulators using E.coli ROS pathway members, and later applied towards understanding Jak/Stat pathway regulation during human progressive kidney disease in glomerular and tubule compartments. The Jak/Stat pathway showed relatively low overlap in supported interactions for the two compartments, though recovered BN+1 genes reflected relevant biological functions and stages of disease progression for the respective kidney compartments. Overall, the results demonstrate that it is possible to refine and expand protein-level signaling pathways using transcriptional microarray data and the introduced expansion and refinement algorithms. The methods are applicable to other biological and computational systems, and are available as publicly-accessible software tools.Ph.D.BioinformaticsUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/89840/1/aphodges_1.pd

Bayesian network analysis of multi-compartmentalized immune responses in a murine model of sepsis and direct lung injury

Abstract Background Inflammatory disease processes involve complex and interrelated systems of mediators. Determining the causal relationships among these mediators becomes more complicated when two, concurrent inflammatory conditions occur. In those cases, the outcome may also be dependent upon the timing, severity and compartmentalization of the insults. Unfortunately, standard methods of experimentation and analysis of data sets may investigate a single scenario without uncovering many potential associations among mediators. However, Bayesian network analysis is able to model linear, nonlinear, combinatorial, and stochastic relationships among variables to explore complex inflammatory disease systems. In these studies, we modeled the development of acute lung injury from an indirect insult (sepsis induced by cecal ligation and puncture) complicated by a direct lung insult (aspiration). To replicate multiple clinical situations, the aspiration injury was delivered at different severities and at different time intervals relative to the septic insult. For each scenario, we measured numerous inflammatory cell types and cytokines in samples from the local compartments (peritoneal and bronchoalveolar lavage fluids) and the systemic compartment (plasma). We then analyzed these data by Bayesian networks and standard methods. Results Standard data analysis demonstrated that the lung injury was actually reduced when two insults were involved as compared to one lung injury alone. Bayesian network analysis determined that both the severity of lung insult and presence of sepsis influenced neutrophil recruitment and the amount of injury to the lung. However, the levels of chemoattractant cytokines responsible for neutrophil recruitment were more strongly linked to the timing and severity of the lung insult compared to the presence of sepsis. This suggests that something other than sepsis-driven exacerbation of chemokine levels was influencing the lung injury, contrary to previous theories. Conclusions To our knowledge, these studies are the first to use Bayesian networks together with experimental studies to examine the pathogenesis of sepsis-associated lung injury. Compared to standard statistical analysis and inference, these analyses elucidated more intricate relationships among the mediators, immune cells and insult-related variables (timing, compartmentalization and severity) that cause lung injury. Bayesian networks are an effective tool for evaluating complex models of inflammation.http://deepblue.lib.umich.edu/bitstream/2027.42/113666/1/13104_2015_Article_1488.pd

Bayesian Network Expansion Identifies New ROS and Biofilm Regulators

Signaling and regulatory pathways that guide gene expression have only been partially defined for most organisms. However, given the increasing number of microarray measurements, it may be possible to reconstruct such pathways and uncover missing connections directly from experimental data. Using a compendium of microarray gene expression data obtained from Escherichia coli, we constructed a series of Bayesian network models for the reactive oxygen species (ROS) pathway as defined by EcoCyc. A consensus Bayesian network model was generated using those networks sharing the top recovered score. This microarray-based network only partially agreed with the known ROS pathway curated from the literature and databases. A top network was then expanded to predict genes that could enhance the Bayesian network model using an algorithm we termed ‘BN+1’. This expansion procedure predicted many stress-related genes (e.g., dusB and uspE), and their possible interactions with other ROS pathway genes. A term enrichment method discovered that biofilm-associated microarray data usually contained high expression levels of both uspE and gadX. The predicted involvement of gene uspE in the ROS pathway and interactions between uspE and gadX were confirmed experimentally using E. coli reporter strains. Genes gadX and uspE showed a feedback relationship in regulating each other's expression. Both genes were verified to regulate biofilm formation through gene knockout experiments. These data suggest that the BN+1 expansion method can faithfully uncover hidden or unknown genes for a selected pathway with significant biological roles. The presently reported BN+1 expansion method is a generalized approach applicable to the characterization and expansion of other biological pathways and living systems

Presence of Putative Repeat-in-Toxin Gene tosA in Escherichia coli Predicts Successful Colonization of the Urinary Tract

Uropathogenic Escherichia coli (UPEC) strains, which cause the majority of uncomplicated urinary tract infections (UTIs), carry a unique assortment of virulence or fitness genes. However, no single defining set of virulence or fitness genes has been found in all strains of UPEC, making the differentiation between UPEC and fecal commensal strains of E. coli difficult without the use of animal models of infection or phylogenetic grouping. In the present study, we consider three broad categories of virulence factors simultaneously to better define a combination of virulence factors that predicts success in the urinary tract. A total of 314 strains of E. coli, representing isolates from fecal samples, asymptomatic bacteriuria, complicated UTIs, and uncomplicated bladder and kidney infections, were assessed by multiplex PCR for the presence of 15 virulence or fitness genes encoding adhesins, toxins, and iron acquisition systems. The results confirm previous reports of gene prevalence among isolates from different clinical settings and identify several new patterns of gene associations. One gene, tosA, a putative repeat-in-toxin (RTX) homolog, is present in 11% of fecal strains but 25% of urinary isolates. Whereas tosA-positive strains carry an unusually high number (11.2) of the 15 virulence or fitness genes, tosA-negative strains have an average of only 5.4 virulence or fitness genes. The presence of tosA was predictive of successful colonization of a murine model of infection, even among fecal isolates, and can be used as a marker of pathogenic strains of UPEC within a distinct subset of the B2 lineage

From Basile to Barbie. Doll fantasies, toy princesses, and clockwork females

Few studies quantify spinal posture behaviour at both the thoracolumbar and lumbar spinal regions. This study compared spontaneous spinal posture in 50 asymptomatic participants ( 21 males ) during three conditions: 10-min computer task in sitting ( participants naïve to the measure ), during their perceived ‘correct’ sitting posture, and standing. Three-dimensional optical tracking quantified surface spinal angles at the thoracolumbar and lumbar regions, and spinal orientation with respect to the vertical. Despite popular belief that lordotic lumbar angles are ‘correct’ for sitting, this was rarely adopted for 10-min sitting. In 10-min sitting, spinal angles flexed 24( 7–9 )deg at lumbar and 12( 6–8 )deg at thoracolumbar regions relative to standing ( P < 0.001 ). When participants ‘corrected’ their sitting posture, their thoracolumbar angle −2( 7 )deg was similar to the angle in standing −1( 6 )deg ( P = 1.00 ). Males were flexed at the lumbar angle relative to females for 10-min sitting, ‘correct’ sitting and standing, but showed no difference at the thoracolumbar region

Different ways to balance the spine in sitting: Muscle activity in specific postures differs between individuals with and without a history of back pain in sitting

Previous research explored muscle activity in four distinct sitting postures with fine-wire electromyography, and found that lumbar multifidus muscle activity increased incrementally between sitting with flat thoracolumbar and lumbar regions, long thoracolumbar lordosis, or short lordosis confined to the lumbar region. This study used similar methods to explore whether people with a history of low back pain provoked by prolonged sitting used different patterns of trunk muscle activity in specific postures.Fine-wire electromyography electrodes were inserted into the right lumbar multifidus (deep and superficial), iliocostalis (lateral and medial), longissimus thoracis and transversus abdominis muscles. Superficial abdominal muscle activity was recorded with surface or fine-wire electrodes. Electromyography amplitude was compared between postures for the back pain group and observations were contrasted with the changes previously reported for pain-free controls. For comparison between groups normalised and non-normalised electromyography amplitudes were compared.Individuals with a history of back pain demonstrated greater activity of the longissimus thoracis muscle in the long lordosis compared with the flat posture [mean difference (95% CI): 46.6 (17.5-75.7)%, normalised to sitting posture peak activity], but pain-free participants did not [mean difference: 7.7 (minus 12-27.6)%]. Pain-free participants modulated lumbar multifidus activity with changes in lumbar curve, but people with a history of pain in prolonged sitting did not change multifidus activity between the long and short lordotic postures.In clinical ergonomic interventions that modify spinal curves and sagittal balance in sitting, the muscle activity used in those postures may differ between people with and without a history of back pain

Traintracks Through Calabi-Yaus: Amplitudes Beyond Elliptic Polylogarithms

We describe a family of finite, four-dimensional, $L$-loop Feynman integrals that involve weight-$(L+1)$ hyperlogarithms integrated over $(L-1)$-dimensional elliptically fibered varieties we conjecture to be Calabi-Yau. At three loops, we identify the relevant K3 explicitly; and we provide strong evidence that the four-loop integral involves a Calabi-Yau threefold. These integrals are necessary for the representation of amplitudes in many theories---from massless $\varphi^4$ theory to integrable theories including maximally supersymmetric Yang-Mills theory in the planar limit---a fact we demonstrate.Comment: 4+2 pages, 4 figures; references adde

Evaluating the Ability of Constructed Intertidal Eastern Oyster (\u3ci\u3eCrassostrea virginica\u3c/i\u3e) Reefs to Address Shoreline Erosion in South Carolina

The application of nature-based solutions to address shoreline erosion and the loss of salt marsh in coastal South Carolina has centered around the creation of intertidal oyster (Crassostrea virginica) reefs that act as natural breakwaters. The installation of such living shoreline materials often results in a rapid accumulation of fine sediments, followed by wild oyster recruitment to suitable materials, and then more gradually the growth of salt marshes (primarily Spartina alterniflora). Leveraging more than two decades of oyster reef restoration and living shorelines research at the South Carolina Department of Natural Resources, this study quantitatively assessed performance rates for both percent oyster cover and marsh protection in relation to reef age. Determining such rates will serve to inform the expectations of prospective adopters of living shorelines as to the timeframes of some of the biological processes, as measures of performance success, that will occur following material installation. Performance success was investigated in terms of recruitment of oysters to installed materials and the creation of new marsh habitat or protection of existing marsh from erosion. Reef age was an important determinant of reef “success”, with significant relationships between reef age and both performance success metrics. Percent oyster cover reached 40% by two years post-installation and 50% by four years post-installation, indicative of high rates of oyster recruitment. The relative marsh protection rate of living shorelines compared to unprotected reference plots was 0.4 m yr-1 Reef performance differed based on bank substrate firmness, bank width, shoreline morphology, and location relative to the Intracoastal Waterway (ICW). Firmer bank substrate was associated with greater percent oyster cover. Broader bank width was associated with greater marsh protection. Higher percent oyster cover measurements were observed on straight, natural shorelines and reefs located along the ICW. Reefs located on the ICW were also associated with greater marsh protection than reefs at non-ICW sites. Further, this study demonstrates that bagged oyster shell reefs are capable of providing shoreline protection services for more than a decade and can endure multiple intense storm events. The results of this study were also used to facilitate the implementation of new living shoreline regulations in coastal South Carolina in the hope of broadening adoption of this approach to addressing shoreline erosion and salt marsh habitat loss

Comparison of a manual and an automated tracking method for Tibetan Plateau vortices

Tibetan Plateau vortices (TPVs) are mesoscale cyclones originating over the Tibetan Plateau (TP) during the extended summer season (April-September). Most TPVs stay on the TP while a small number can move off the TP to the east. TPVs are known to be one of the main precipitation-bearing systems on the TP and moving-off TPVs have been associated with heavy precipitation and flooding downstream of the TP (e.g. Sichuan province, Yangtze River Valley). Identifying and tracking TPVs is difficult both due to their comparatively small horizontal extent (400 – 800 km) and the limited availability of soundings over the TP, which, in turn, constitutes a challenge for short-term predictions of TPV-related impacts and for the climatological study of TPVs. In this study, (i) manual tracking (MT) results using radiosonde data from a network over and downstream of the TP are compared with (ii) results obtained by an automated tracking (AT) algorithm applied to ERA-Interim reanalysis. Ten MT-TPV cases are selected based on method (i) and matched to and compared with the corresponding AT-TPVs identified with method (ii). Conversely, ten AT-TPVs are selected and compared with the corresponding MT-TPVs. In general, the comparison shows good results in cases where the underlying data are in good agreement, but considerable differences are also seen in some cases and explained in terms of differences in the tracking methods, data availability/coverage and disagreement between sounding and ERA-Interim data. Recommendations are given for future efforts in TPV detection and tracking, including in an operational weather forecasting context