A Translational Study of the Correlation Between Low Birth Weight, Hypertension, and Kidney Function Using a Rat Model

We studied the correlation between low birth weight, hypertension, and kidney function using a rat model. There is a strong correlation between these three phenomena especially in the Southeastern United States and in non-White populations. We hypothesized that the anti-hypertensive drugs Reserpine and Hydralazine would prevent hypertension and improve renal function in low birth weight rats. We used a rat model created by Dr. Barbara Alexander in this study. Pregnant rats were subjected to Reduced Uterine Perfusion Pressure surgery. Silver clips were placed on the abdominal aorta and uterine arteries approximately two weeks after fertilization in order to restrict blood flow to the developing fetus. The reduced nutrient availability results in slower fetal development and low birth weight offspring. Two drugs with effects on cardiovascular function were used to lower blood pressure. Hydralazine was administered via drinking water at a dose of 80mg/L initiated at 6 weeks of age until the end experiment at 12 weeks of age. Reserpine was administered via drinking water at a dose of 5mg/L initiated at 6 weeks of age until the end of experiments at 12 weeks of age. Administration of this medication constituted the “treated” rats. At 12 weeks of age, catheters were inserted to measure blood pressure and glomerular filtration rate was calculated. Mild schemia reperfusion was performed to see how the kidneys reacted to mild stress. We found that the uterine restricted rats had normal gestations, but weighted significantly less than the controls at birth. The rats gained weight at the same rate and weighed the same at the end of the study. As expected, low birth weight untreated offspring had higher blood pressure than any other group. Surprisingly, GFR/g in the uterine-restricted, unstressed, untreated animals was not significantly higher, as predicted from both the higher MAP and presumably lower nephron number in these rats. Thus, there was no evidence of significant hyperfiltration occurring, and so this seemingly cannot explain the hypertension which developed. Based on this study, I would advocate using low birth weight as a biomarker for elevated risk of hypertension and kidney disease

Writing fast models in Swarm

Execution performance is an important practical issue for agent based modeling. This document traces the path of a Java Swarm model from performance profiling and evaluation through to redesign and reimplementation of a much faster sibling model. This document is available on the World Wide Web (http://www.santafe.edu/~mgd/swarmfest2000/performance.html). Additional example code is available here (ftp://ftp.swarm.org/pub/swarm/src/users-contrib/anarchy/java_performance-0.0.tar.gz)

A coarse-grained model for synergistic action of multiple enzymes on cellulose

Background Degradation of cellulose to glucose requires the cooperative action of three classes of enzymes, collectively known as cellulases. Endoglucanases randomly bind to cellulose surfaces and generate new chain ends by hydrolyzing β-1,4-D-glycosidic bonds. Exoglucanases bind to free chain ends and hydrolyze glycosidic bonds in a processive manner releasing cellobiose units. Then, β-glucosidases hydrolyze soluble cellobiose to glucose. Optimal synergistic action of these enzymes is essential for efficient digestion of cellulose. Experiments show that as hydrolysis proceeds and the cellulose substrate becomes more heterogeneous, the overall degradation slows down. As catalysis occurs on the surface of crystalline cellulose, several factors affect the overall hydrolysis. Therefore, spatial models of cellulose degradation must capture effects such as enzyme crowding and surface heterogeneity, which have been shown to lead to a reduction in hydrolysis rates. Results We present a coarse-grained stochastic model for capturing the key events associated with the enzymatic degradation of cellulose at the mesoscopic level. This functional model accounts for the mobility and action of a single cellulase enzyme as well as the synergy of multiple endo- and exo-cellulases on a cellulose surface. The quantitative description of cellulose degradation is calculated on a spatial model by including free and bound states of both endo- and exo-cellulases with explicit reactive surface terms (e.g., hydrogen bond breaking, covalent bond cleavages) and corresponding reaction rates. The dynamical evolution of the system is simulated by including physical interactions between cellulases and cellulose. Conclusions Our coarse-grained model reproduces the qualitative behavior of endoglucanases and exoglucanases by accounting for the spatial heterogeneity of the cellulose surface as well as other spatial factors such as enzyme crowding. Importantly, it captures the endo-exo synergism of cellulase enzyme cocktails. This model constitutes a critical step towards testing hypotheses and understanding approaches for maximizing synergy and substrate properties with a goal of cost effective enzymatic hydrolysis

Definition of the Viral Targets of Protective HIV-1-Specific T Cell Responses

Background: The efficacy of the CTL component of a future HIV-1 vaccine will depend on the induction ofresponses with the most potent antiviral activity and broad HLA class I restriction. However, current HIV vaccinedesigns are largely based on viral sequence alignments only, not incorporating experimental data on T cellfunction and specificity. Methods: Here, 950 untreated HIV-1 clade B or -C infected individuals were tested for responses to sets of 410overlapping peptides (OLP) spanning the entire HIV-1 proteome. For each OLP, a “protective ratio” (PR) wascalculated as the ratio of median viral loads (VL) between OLP non-responders and responders. Results: For both clades, there was a negative relationship between the PR and the entropy of the OLP sequence.There was also a significant additive effect of multiple responses to beneficial OLP. Responses to beneficial OLPwere of significantly higher functional avidity than responses to non-beneficial OLP. They also had superior in-vitroantiviral activities and, importantly, were at least as predictive of individuals’ viral loads than their HLA class Igenotypes. Conclusions: The data thus identify immunogen sequence candidates for HIV and provide an approach for T cellimmunogen design applicable to other viral infections

A quantitative model of trading and price formation in financial markets

We use standard physics techniques to model trading and price formation in a market under the assumption that order arrival and cancellations are Poisson random processes. This model makes testable predictions for the most basic properties of a market, such as the diffusion rate of prices, which is the standard measure of financial risk, and the spread and price impact functions, which are the main determinants of transaction cost. Guided by dimensional analysis, simulation, and mean field theory, we find scaling relations in terms of order flow rates. We show that even under completely random order flow the need to store supply and demand to facilitate trading induces anomalous diffusion and temporal structure in prices.Comment: 5 pages, 4 figure

Historical geography II: traces remain

The second report in this series turns to focus on the trace in relation to life-writing and biography in historical geography and beyond. Through attention to tracing journeys, located moments and listening to the presence of ghosts (Ogborn, 2005), this report seeks to highlight the range of different ways in which historical geographers have explored lives, deaths, and their transient traces through varied biographical terrains. Continuing to draw attention in historical geography to the darkest of histories, this piece will pivot on moments of discovering the dead to showcase the nuanced ways in which historical geography is opening doors into uncharted lives and unspoken histories

Genital Tract Sequestration of SIV following Acute Infection

We characterized the evolution of simian immunodeficiency virus (SIV) in the male genital tract by examining blood- and semen-associated virus from experimentally and sham vaccinated rhesus monkeys during primary infection. At the time of peak virus replication, SIV sequences were intermixed between the blood and semen supporting a scenario of high-level virus "spillover" into the male genital tract. However, at the time of virus set point, compartmentalization was apparent in 4 of 7 evaluated monkeys, likely as a consequence of restricted virus gene flow between anatomic compartments after the resolution of primary viremia. These findings suggest that SIV replication in the male genital tract evolves to compartmentalization after peak viremia resolves

A Signature in HIV-1 Envelope Leader Peptide Associated with Transition from Acute to Chronic Infection Impacts Envelope Processing and Infectivity

Mucosal transmission of the human immunodeficiency virus (HIV) results in a bottleneck in viral genetic diversity. Gnanakaran and colleagues used a computational strategy to identify signature amino acids at particular positions in Envelope that were associated either with transmitted sequences sampled very early in infection, or sequences sampled during chronic infection. Among the strongest signatures observed was an enrichment for the stable presence of histidine at position 12 at transmission and in early infection, and a recurrent loss of histidine at position 12 in chronic infection. This amino acid lies within the leader peptide of Envelope, a region of the protein that has been shown to influence envelope glycoprotein expression and virion infectivity. We show a strong association between a positively charged amino acid like histidine at position 12 in transmitted/founder viruses with more efficient trafficking of the nascent envelope polypeptide to the endoplasmic reticulum and higher steady-state glycoprotein expression compared to viruses that have a non-basic position 12 residue, a substitution that was enriched among viruses sampled from chronically infected individuals. When expressed in the context of other viral proteins, transmitted envelopes with a basic amino acid position 12 were incorporated at higher density into the virus and exhibited higher infectious titers than did non-signature envelopes. These results support the potential utility of using a computational approach to examine large viral sequence data sets for functional signatures and indicate the importance of Envelope expression levels for efficient HIV transmission

Early-life soy exposure and age at menarche

This study examines the timing of menarche in relation to infant-feeding methods, specifically addressing the potential effects of soy isoflavone exposure through soy-based infant feeding. Subjects were participants in the Avon Longitudinal Study of Parents and Children (ALSPAC). Mothers were enrolled during pregnancy and their children have been followed prospectively. Early-life feeding regimes, categorised as primarily breast, early formula, early soy and late soy, were defined using infant-feeding questionnaires administered during infancy. For this analysis, age at menarche was assessed using questionnaires administered approximately annually between ages 8 and 14.5. Eligible subjects were limited to term, singleton, White females. We used Kaplan-Meier survival curves and Cox proportional hazards models to assess age at menarche and risk of menarche over the study period. The present analysis included 2920 girls. Approximately 2% of mothers reported that soy products were introduced into the infant diet at or before 4 months of age (early soy). The median age at menarche [interquartile range (IQR)] in the study sample was 153 months [144-163], approximately 12.8 years. The median age at menarche among early soy-fed girls was 149 months (12.4 years) [IQR, 140-159]. Compared with girls fed non-soy-based infant formula or milk (early formula), early soy-fed girls were at 25% higher risk of menarche throughout the course of follow-up (hazard ratio 1.25 [95% confidence interval 0.92, 1.71]). Our results also suggest that girls fed soy products in early infancy may have an increased risk of menarche specifically in early adolescence. These findings may be the observable manifestation of mild endocrine-disrupting effects of soy isoflavone exposure. However, our study is limited by few soy-exposed subjects and is not designed to assess biological mechanisms. Because soy formula use is common in some populations, this subtle association with menarche warrants more in-depth evaluation in future studies

Evidence of Differential HLA Class I-Mediated Viral Evolution in Functional and Accessory/Regulatory Genes of HIV-1

Despite the formidable mutational capacity and sequence diversity of HIV-1, evidence suggests that viral evolution in response to specific selective pressures follows generally predictable mutational pathways. Population-based analyses of clinically derived HIV sequences may be used to identify immune escape mutations in viral genes; however, prior attempts to identify such mutations have been complicated by the inability to discriminate active immune selection from virus founder effects. Furthermore, the association between mutations arising under in vivo immune selection and disease progression for highly variable pathogens such as HIV-1 remains incompletely understood. We applied a viral lineage-corrected analytical method to investigate HLA class I-associated sequence imprinting in HIV protease, reverse transcriptase (RT), Vpr, and Nef in a large cohort of chronically infected, antiretrovirally naïve individuals. A total of 478 unique HLA-associated polymorphisms were observed and organized into a series of “escape maps,” which identify known and putative cytotoxic T lymphocyte (CTL) epitopes under selection pressure in vivo. Our data indicate that pathways to immune escape are predictable based on host HLA class I profile, and that epitope anchor residues are not the preferred sites of CTL escape. Results reveal differential contributions of immune imprinting to viral gene diversity, with Nef exhibiting far greater evidence for HLA class I-mediated selection compared to other genes. Moreover, these data reveal a significant, dose-dependent inverse correlation between HLA-associated polymorphisms and HIV disease stage as estimated by CD4+ T cell count. Identification of specific sites and patterns of HLA-associated polymorphisms across HIV protease, RT, Vpr, and Nef illuminates regions of the genes encoding these products under active immune selection pressure in vivo. The high density of HLA-associated polymorphisms in Nef compared to other genes investigated indicates differential HLA class I-driven evolution in different viral genes. The relationship between HLA class I-associated polymorphisms and lower CD4+ cell count suggests that immune escape correlates with disease status, supporting an essential role of maintenance of effective CTL responses in immune control of HIV-1. The design of preventative and therapeutic CTL-based vaccine approaches could incorporate information on predictable escape pathways