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Biomedical subjects

James Taylor

Publications and source records attributed to James Taylor.

At least 19 recordsLinked to original sources
PubMed2007

Dark matter maps reveal cosmic scaffolding.

Ordinary baryonic particles (such as protons and neutrons) account for only one-sixth of the total matter in the Universe. The remainder is a mysterious 'dark matter' component, which does not interact via electromagnetism and thus neither emits nor reflects light. As dark matter cannot be seen directly using traditional observations, very little is currently known about its properties. It does interact via gravity, and is most effectively probed through gravitational lensing: the deflection of light from distant galaxies by the gravitational attraction of foreground mass concentrations. This is a purely geometrical effect that is free of astrophysical assumptions and sensitive to all matter--whether baryonic or dark. Here we show high-fidelity maps of the large-scale distribution of dark matter, resolved in both angle and depth. We find a loose network of filaments, growing over time, which intersect in massive structures at the locations of clusters of galaxies. Our results are consistent with predictions of gravitationally induced structure formation, in which the initial, smooth distribution of dark matter collapses into filaments then into clusters, forming a gravitational scaffold into which gas can accumulate, and stars can be built.

Journal Article↗
PubMed2006

ESPERR: learning strong and weak signals in genomic sequence alignments to identify functional elements.

Genomic sequence signals - such as base composition, presence of particular motifs, or evolutionary constraint - have been used effectively to identify functional elements. However, approaches based only on specific signals known to correlate with function can be quite limiting. When training data are available, application of computational learning algorithms to multispecies alignments has the potential to capture broader and more informative sequence and evolutionary patterns that better characterize a class of elements. However, effective exploitation of patterns in multispecies alignments is impeded by the vast number of possible alignment columns and by a limited understanding of which particular strings of columns may characterize a given class. We have developed a computational method, called ESPERR (evolutionary and sequence pattern extraction through reduced representations), which uses training examples to learn encodings of multispecies alignments into reduced forms tailored for the prediction of chosen classes of functional elements. ESPERR produces a greatly improved Regulatory Potential score, which can discriminate regulatory regions from neutral sites with excellent accuracy ( approximately 94%). This score captures strong signals (GC content and conservation), as well as subtler signals (with small contributions from many different alignment patterns) that characterize the regulatory elements in our training set. ESPERR is also effective for predicting other classes of functional elements, as we show for DNaseI hypersensitive sites and highly conserved regions with developmental enhancer activity. Our software, training data, and genome-wide predictions are available from our Web site (http://www.bx.psu.edu/projects/esperr).

Algorithms↗
PubMed2006

Experimental validation of predicted mammalian erythroid cis-regulatory modules.

Multiple alignments of genome sequences are helpful guides to functional analysis, but predicting cis-regulatory modules (CRMs) accurately from such alignments remains an elusive goal. We predict CRMs for mammalian genes expressed in red blood cells by combining two properties gleaned from aligned, noncoding genome sequences: a positive regulatory potential (RP) score, which detects similarity to patterns in alignments distinctive for regulatory regions, and conservation of a binding site motif for the essential erythroid transcription factor GATA-1. Within eight target loci, we tested 75 noncoding segments by reporter gene assays in transiently transfected human K562 cells and/or after site-directed integration into murine erythroleukemia cells. Segments with a high RP score and a conserved exact match to the binding site consensus are validated at a good rate (50%-100%, with rates increasing at higher RP), whereas segments with lower RP scores or nonconsensus binding motifs tend to be inactive. Active DNA segments were shown to be occupied by GATA-1 protein by chromatin immunoprecipitation, whereas sites predicted to be inactive were not occupied. We verify four previously known erythroid CRMs and identify 28 novel ones. Thus, high RP in combination with another feature of a CRM, such as a conserved transcription factor binding site, is a good predictor of functional CRMs. Genome-wide predictions based on RP and a large set of well-defined transcription factor binding sites are available through servers at http://www.bx.psu.edu/.

Amino Acid Motifs↗
PubMed2006

Short course of systemic corticosteroids in sinonasal polyposis: a double-blind, randomized, placebo-controlled trial with evaluation of outcome measures.

BACKGROUND: Topical and systemic corticosteroids are the first choice in medical treatments for sinonasal polyposis, but surprisingly, there is no high-level evidence for the efficacy of oral corticosteroids. OBJECTIVE: The aim of this study was to establish the efficacy of a short course of oral prednisolone in ameliorating the symptoms of sinonasal polyposis, as well as reducing mucosal inflammation assessed by means of nasendoscopy and magnetic resonance imaging (MRI). A secondary aim was to evaluate the relationship between outcome measures. METHODS: Subjects with symptomatic endoscopically diagnosed sinonasal polyposis received 50 mg of prednisolone daily for 14 days or placebo. Outcome was quantified by using the modified 31-item Rhinosinusitis Outcome Measure questionnaire, physician's assessment, nasendoscopy with photography, and MRI. RESULTS: There were 20 subjects in each treatment group. Only the prednisolone-treated group showed significant improvement in nasal symptoms (P < .001). The Rhinosinusitis Outcome Measure score improved in both groups, but the prednisolone-treated group had significantly greater improvement than the placebo group (P < .001). Objectively, there was significant reduction in polyp size, as noted with nasendoscopy (P < .001) and MRI (P < .001), only in the prednisolone-treated group. The outcome measures correlated with each other; the highest level of correlation was between the objective measures of nasendoscopy and MRI (R(2) = 0.76, P < .001). There were no significant adverse events. CONCLUSION: This trial clearly establishes clinically significant improvement in the symptoms and pathology of sinonasal polyposis with a short course of systemic corticosteroids. MRI scanning and quantitative nasendoscopic photography are objective and valid tools for assessing the outcome of treatment in this condition. CLINICAL IMPLICATIONS: A 14-day course of 50 mg of prednisolone is safe and effective therapy for symptomatic nasal polyposis.

Adult↗
PubMed2006

Cerebrovascular disease associated with sickle cell pulmonary hypertension.

In patients with sickle cell disease, anemia is a recognized risk factor for stroke, death, and the development of pulmonary hypertension. We have proposed that hemolytic anemia results in endothelial dysfunction and vascular instability and can ultimately lead to a proliferative vasculopathy leading to pulmonary hypertension. Consistent with this mechanism of disease, we now report a case series of six patients with obliterative central nervous system vasculopathy who also have pulmonary hypertension and high hemolytic rate. These patients, identified in the course of a prospective screening study for pulmonary hypertension, presented with neurological symptoms prompting neuroimaging studies. Compared to 164 other patients of similar age in the screened population, those with newly diagnosed or clinically active cerebrovascular disease have significantly lower hemoglobin levels and higher levels of lactate dehydrogenase. A review of the literature suggests that many clinical, epidemiological, and physiological features of the arteriopathy of pulmonary hypertension closely overlap with those of stroke in sickle cell disease, both known to involve proliferative vascular intimal and smooth muscle hypertrophy and thrombosis. These cases suggest that cerebrovascular disease and pulmonary hypertension in sickle cell disease share common mechanisms, in particular, reduced nitric oxide bioactivity associated with particularly high-grade hemolysis. Clinicians should suspect occult cerebrovascular disease in sickle cell patients with pulmonary hypertension.

Adult↗
PubMed2006

Monitoring of distribution water qualities under various source water blending.

The main goal of this large-scale pilot distribution study was to systematically investigate the impacts of blending different source waters on distribution water qualities. The principal source waters investigated were conventionally treated ground water (G1), surface water processed by enhanced treatment (S1), and desalted seawater by reverse osmosis membranes (RO). Due to the nature of raw water quality and associated treatment processes, G1 water had high alkalinity, while S1 and RO sources were characterized as high sulfate and high chloride waters, respectively. One year of pilot pipe study demonstrated that water quality was significantly deteriorated by increased color when source water blends with characteristics different from historic groundwater were introduced to pipe distribution systems. Elevated color was associated with release of iron corrosion products, mainly from aged unlined cast iron pipes. Iron release increased significantly when exposed to RO and S1 waters: that is, the greater iron release was experienced with alkalinity reduced below the background of G1 water. Lead and copper release to water, on the other hand, enhanced with the application of RO and G1 waters, respectively.

Alkalies↗
PubMed2006

Intimo-intimal intussusception of the aorta.

A 50-year-old man presented with acute onset of chest pain. Subsequent transesophageal echocardiography and computed tomography scan showed absence of a flap in the ascending aorta and a clear dissection flap involving the arch and descending aorta. Magnetic resonance imaging showed a tear and a small flap in the right coronary sinus. During surgery, we found a total circumferential intimal tear at the sinotubular junction with intimo-intimal intussusception of the internal channel into the arch. Dissection without intimal flap and aortic intussusception is a rare form of type A dissection, which is difficult to diagnose on routine investigations and can delay treatment.

Aortic Dissection↗
PubMed2006

Impacts of blending ground, surface, and saline waters on lead release in drinking water distribution systems.

The impacts of distribution water quality changes caused by blending different source waters on lead release from corrosion loops containing small lead coupons were investigated in a pilot distribution study. The 1-year pilot study demonstrated that lead release to drinking water increased as chlorides increased and sulfates decreased. Silica and calcium inhibited lead release to a lesser degree than sulfates. An additional 3-month field study isolated and verified the effects of chlorides and sulfates on lead release. Lead release decreased with increasing pH and increasing alkalinity during the 1-year pilot study; however, the effects of pH and alkalinity on lead release, were not clearly elucidated due to confounding effects. A statistical model was developed using nonlinear regression, which showed that lead release increased with increasing chlorides, alkalinity and temperature, and decreased with increasing pH and sulfates. The model indicated that primary treatment processes such as enhanced coagulation and RO (reverse osmosis membrane) were related to lead release by water quality. Chlorides are high in RO-finished water and increase lead release, while sulfates are high following enhanced coagulation and decrease lead release.

Calcium↗
PubMed2005

Lactate dehydrogenase as a biomarker of hemolysis-associated nitric oxide resistance, priapism, leg ulceration, pulmonary hypertension, and death in patients with sickle cell disease.

Pulmonary hypertension is prevalent in adult patients with sickle cell disease and is strongly associated with early mortality and markers of hemolysis, in particular, serum lactate dehydrogenase (LDH). Intravascular hemolysis leads to impaired bioavailability of nitric oxide (NO), mediated by NO scavenging by plasma oxyhemoglobin and by arginine degradation by plasma arginase. We hypothesized that serum LDH may represent a convenient biomarker of intravascular hemolysis and NO bioavailability, characterizing a clinical subphenotype of hemolysis-associated vasculopathy. In a cohort of 213 patients with sickle cell disease, we found statistically significant associations of steady-state LDH with low levels of hemoglobin and haptoglobin and high levels of reticulocytes, bilirubin, plasma hemoglobin, aspartate aminotransferase, arginase, and soluble adhesion molecules. LDH isoenzyme fractionation confirmed predominance of LD1 and LD2, the principal isoforms within erythrocytes. In a subgroup, LDH levels closely correlated with plasma cell-free hemoglobin, accelerated NO consumption by plasma, and impaired vasodilatory responses to an NO donor. Remarkably, this simple biomarker was associated with a clinical subphenotype of pulmonary hypertension, leg ulceration, priapism, and risk of death in patients with sickle cell disease. We propose that LDH elevation identifies patients with a syndrome of hemolysis-associated NO resistance, endothelial dysfunction, and end-organ vasculopathy.

Adult↗
PubMed2005

Strong and weak male mutation bias at different sites in the primate genomes: insights from the human-chimpanzee comparison.

Male mutation bias is a higher mutation rate in males than in females thought to result from the greater number of germ line cell divisions in males. If errors in DNA replication cause most mutations, then the magnitude of male mutation bias, measured as the male-to-female mutation rate ratio (alpha), should reflect the relative excess of male versus female germ line cell divisions. Evolutionary rates averaged among all sites in a sequence and compared between mammalian sex chromosomes were shown to be indeed higher in males than in females. However, it is presently unknown whether individual classes of substitutions exhibit such bias. To address this issue, we investigated male mutation bias separately at non-CpG and CpG sites using human-chimpanzee whole-genome alignments. We observed strong male mutation bias at non-CpG sites: alpha in the X-autosome comparison was approximately 6-7, which was similar to the male-to-female ratio in the number of germ line cell divisions. In contrast, mutations at CpG sites exhibited weak male mutation bias: alpha in the X-autosome comparison was only approximately 2-3. This is consistent with the methylation-induced and replication-independent mechanism of CpG transitions, which constitute the majority of mutations at CpG sites. Interestingly, our study also indicated weak male mutation bias for transversions at CpG sites, implying a spontaneous mechanism largely not associated with replication. Male mutation bias was equally strong at CpG and non-CpG sites located within unmethylated "CpG islands," suggesting the replication-dependent origin of these mutations. Thus, we found that the strength of male mutation bias is nonuniform in the primate genomes. Importantly, we discovered that male mutation bias depends on the proportion of CpG sites in the loci compared. This might explain the differences in the magnitude of primate male mutation bias observed among studies.

Animals↗
PubMed2005

Galaxy: a platform for interactive large-scale genome analysis.

Accessing and analyzing the exponentially expanding genomic sequence and functional data pose a challenge for biomedical researchers. Here we describe an interactive system, Galaxy, that combines the power of existing genome annotation databases with a simple Web portal to enable users to search remote resources, combine data from independent queries, and visualize the results. The heart of Galaxy is a flexible history system that stores the queries from each user; performs operations such as intersections, unions, and subtractions; and links to other computational tools. Galaxy can be accessed at http://g2.bx.psu.edu.

Biological Evolution↗
PubMed2005

Evaluation of regulatory potential and conservation scores for detecting cis-regulatory modules in aligned mammalian genome sequences.

Techniques of comparative genomics are being used to identify candidate functional DNA sequences, and objective evaluations are needed to assess their effectiveness. Different analytical methods score distinctive features of whole-genome alignments among human, mouse, and rat to predict functional regions. We evaluated three of these methods for their ability to identify the positions of known regulatory regions in the well-studied HBB gene complex. Two methods, multispecies conserved sequences and phastCons, quantify levels of conservation to estimate a likelihood that aligned DNA sequences are under purifying selection. A third function, regulatory potential (RP), measures the similarity of patterns in the alignments to those in known regulatory regions. The methods can correctly identify 50%-60% of noncoding positions in the HBB gene complex as regulatory or nonregulatory, with RP performing better than do other methods. When evaluated by the ability to discriminate genomic intervals, RP reaches a sensitivity of 0.78 and a true discovery rate of approximately 0.6. The performance is better on other reference sets; both phastCons and RP scores can capture almost all regulatory elements in those sets along with approximately 7% of the human genome.

Algorithms↗
PubMed2005

MR angiography of aortoiliac occlusive disease: a phase III study of the safety and effectiveness of the blood-pool contrast agent MS-325.

PURPOSE: To evaluate prospectively the safety and effectiveness of aortoiliac magnetic resonance (MR) angiography enhanced with MS-325 (gadofosveset trisodium) at a dose of 0.03 mmol/kg; effectiveness was defined as accuracy relative to the reference standard, conventional angiography. MATERIALS AND METHODS: Study was approved by institutional review boards of participating institutions, and required national approvals were obtained. Study protocol conformed to Good Clinical Practice guidelines, and informed patient consent was obtained. Patients with known or suspected peripheral vascular disease received 0.03 mmol/kg MS-325 for aortoiliac MR angiography. They were also examined with conventional angiography. MS-325-enhanced MR was evaluated for safety and effectiveness. Along with unenhanced two-dimensional time-of-flight MR angiography, it was compared with conventional angiography for presence of vascular stenosis. Student t tests were used to identify significant improvement in diagnostic sensitivity, specificity, and accuracy, as well as quantitative characterization of stenoses by three blinded readers. Correlations between readers of conventional angiograms were calculated and compared with MR results. RESULTS: In 174 patients, MS-325-enhanced MR angiography showed significant improvement (P < or = .001) in sensitivity, specificity, and accuracy for diagnosis of clinically significant (> or =50%) stenosis, compared with unenhanced MR. For all readers, areas under the receiver operating characteristic curve for both quantitative and qualitative measures of significant disease increased (P < .001) for MS-325-enhanced MR compared with time-of-flight MR. All readers also expressed higher confidence in diagnosis (P < .001) and found fewer images uninterpretable with MS-325 enhancement. All measures of interpretation accuracy approached corresponding measures of correlation between readers of conventional angiograms. Incidence of severe and serious adverse events with MS-325 was low. No patients were withdrawn from study due to adverse events or abnormalities in laboratory results. There were no clinically important trends in findings at hematology, blood chemistry, urinalysis, electrocardiography, or physical examination. CONCLUSION: MR angiography with MS-325 provides significant improvement in effectiveness over unenhanced MR (and minimal and transient side effects) at a dose of 0.03 mmol/kg and was safe and effective for MR evaluation of patients with aortoiliac occlusive disease.

Adult↗
PubMed2005

Combined influence of membrane surface properties and feed water qualities on RO/NF mass transfer, a pilot study.

The impact of membrane surface characteristics and NOM on membrane performance has been investigated for varying pretreatment and membranes in a field study. Surface charge, hydrophobicity and roughness varied significantly among the four membranes used in the study. The membranes were tested in parallel following two different pretreatment processes, an enhanced Zenon ultrafiltration process (ZN) and a compact CSF process (Superpulsator (SP)) prior to RO membrane treatment for a total of eight integrated membrane systems. All membrane systems were exposed to the similar temperature, recovery and flux as well as chemical dosage. The membrane feed water qualities were statistically equivalent following ZN pretreatment and SP pretreatment except for NOM and SUVA. Membrane surface characteristics, NOM and SUVA measurements were used to describe mass transfer in a low-pressure RO integrated membrane system. Solute and water mass transfer coefficients (MTCs) were investigated for dependence on membrane surface properties and NOM mass loading. Inorganic MTCs were accurately described by a Gaussian distribution curve. Water productivity decreased with NOM loading and increased with contact angle and roughness. The negative effects of NOM loading on productivity were reduced as the negative charge on the membrane surface increased. Inorganic MTCs were also correlated to surface hydrophobicity and surface roughness. The permeability change of identical membranes was related to NOM loading, hydrophobicity and roughness. Organic fouling as measured by water, organic and inorganic mass transfer was less for membranes with higher hydrophilicity and roughness.

Flocculation↗
PubMed2005

Predicting prolonged dysphagia in acute stroke: the Royal Adelaide Prognostic Index for Dysphagic Stroke (RAPIDS).

Dysphagia is common after stroke and is associated with increased morbidity and mortality. Predicting those who are likely to have significant prolonged dysphagia is not possible at present. This study was undertaken to validate the Royal Adelaide Prognostic Index for Dysphagic Stroke (RAPIDS) in the prediction of prolonged dysphagia following acute stroke using clinical and radiographic features. A prospective study of unselected, consecutive admissions to the Royal Adelaide Hospital acute stroke unit was undertaken. Clinical and radiographic features applicable to the RAPIDS test were calculated and the sensitivity, specificity, and likelihood ratio for predicting prolonged dysphagia were calculated with 95% confidence intervals (CI). Of 104 subjects admitted with acute stroke, 55 (53%) had dysphagia and 20 (19%) had dysphagia requiring nonoral feeding/hydration for 14 days or more or died while dysphagic prior to 14 days. The RAPIDS test had sensitivity of 90% (95% CI = 70-97%) and specificity of 92% (95% CI - 84-96%) for predicting this latter group of patients. We conclude that the RAPIDS test can be used early to identify patients likely to have prolonged dysphagia. This test could form a basis for selection of patients for trials of nonoral feeding methods.

Acute Disease↗
PubMed2005

Clues to function in gene deserts.

Recent work by Ivan Ovcharenko and colleagues has shed new light on the functional importance of gene deserts. They demonstrate that sequence conservation levels separate gene deserts into stable (more conserved) and variable classes. Both classes exhibit characteristics suggestive of function. The stable deserts in particular show features suggesting a role in the complex regulation of core vertebrate genes.

DNA, Intergenic↗
PubMed2004

Gene expression profiling in human preadipocytes and adipocytes by microarray analysis.

Uncontrolled expansion of adipose tissue leads to obesity, a public health epidemic affecting >30% of adult Americans. Adipose mass increases in part through the recruitment and differentiation of an existing pool of preadipocytes (PA) into adipocytes (AD). Most studies investigating adipogenesis used primarily murine cell lines; much less is known about the relevant processes that occur in humans. Therefore, characterization of genes associated with adipocyte development is key to understanding the pathogenesis of obesity and developing treatments for this disorder. To address this issue, we performed large-scale analyses of human adipose gene expression using microarray technology. Differential gene expression between PA and AD was analyzed in 6 female patients using human cDNA microarray slides and data analyzed using the Stanford Microarray Database. Statistical analysis for the gene expression was performed using the SAS mixed models. Compared with PA, several genes involved in lipid metabolism were overexpressed in AD, including fatty acid binding protein, adipose differentiation-related protein, lipoprotein lipase, perilipin, and adipose most abundant transcript 1. Novel genes expressed in adipocytes included E2F5 transcriptional factor and SMARC (SWI/SNF-related, matrix associated, actin-dependent regulator of chromatin). PA predominantly expressed genes encoding extracellular matrix components such as fibronectin, matrix metalloprotein, and novel proteins such as lysyl oxidase. Despite the high differential expression of some of these genes, many did not differ significantly likely due to high variability and limited statistical power. A comprehensive list of differential gene expression is presented according to cellular function. In conclusion, these studies offer an overview of the gene expression profiles in PA and AD and identify new genes with potentially important functions in adipose tissue development and obesity that merit further investigation.

Adipocytes↗