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Marine invertebrates exhibit broad diversity in developmental form and life-history mode. Efforts to understand the origins of this diversity have focused on processes that underlie transitions between modes. One widespread transition has involved the evolution of a morphologically simplified, non-feeding larval form from a morphologically complex feeding larva. This transition has been inferred in diverse taxa where both modes of development are known from closely-related species. There are, however, few examples of clades that include both modes of development as well as functionally-intermediate stages in the transition between them. The brittlestar genus Macrophiothrix is species-rich and common in certain Indo-west Pacific coral reef habitats. Twelve species at Lizard Island, Australia are similar as adults but vary more than 60-fold in average egg volume, and egg size is correlated with a suite of traits involving size, form, growth, and timing. In addition, early life-history stages in the genus include simple non-feeding larvae, complex feeding larvae, and two larval forms that are functionally intermediate. Diversity of larval form and function in Macrophiothrix provides evidence of a life-history transition involving sequential changes in morphology, feeding necessity, and feeding capacity that are resolvable in evolutionary time. Estimates of times to metamorphosis also allow a comparison of the ecological conditions under which different egg sizes, and their associated life-history modes, would be favored by selection.

Cercospora carotae and Alternaria dauci cause foliar blight on carrot (Daucus carota subsp. sativus) and are managed with fungicides to prevent yield loss. Sprays are initiated prior to disease symptoms and reapplied frequently, but some of these applications may not be necessary when the threat of disease is low. Delaying the initial fungicide spray until disease symptoms are observed and applying subsequent sprays according to the TOM-CAST disease forecaster may reduce fungicide inputs. The objective of this 2-year field study was to compare preventive, calendar-based application schedules with an integrated management approach that incorporates disease scouting to initiate fungicide application and the TOM-CAST system for timing subsequent fungicide sprays to manage foliar blight on processing, fresh market, and cut-and-peel carrot cultivars in Michigan. Applications of the fungicides chlorothalonil alternated with azoxy-strobin were made prior to disease symptoms (0% blight) or when the foliage became blighted at a trace, 5%, or 10% severity level. Fungicides were reapplied every 7 or 10 days or according to TOM-CAST using disease severity value (DSV) thresholds of 15, 20, or 25. Initiating fungicide treatment at a trace level of disease and timing subsequent sprays according to the TOM-CAST 15-DSV forecaster was comparable to the preventive, calendar-based fungicide regime. One to five fewer applications were needed, while fungicide costs were reduced by $21 to $141 per hectare, when spraying at the trace disease threshold and reapplying according to the TOM- CAST 15-DSV program compared with the 7- or 10-day intervals initiated at 0% blight. Fungicide programs initiated at 5 or 10% leaf blight often provided less control than programs initiated at 0% and trace disease. This study highlights the importance of initiating a fungicide program prior to advanced foliar blight and validates the TOM-CAST 15-DSV forecaster for managing Cercospora leaf spot and Alternaria leaf blight in three carrot production systems. [ABSTRACT FROM AUTHOR]

Abstract Background Infection with high-risk type human papilloma viruses (HPVs) is associated with cervical carcinomas and with a subset of head and neck squamous cell carcinomas. Viral E6 and E7 oncogenes cooperate to achieve cell immortalization by a mechanism that is not yet fully understood. Here, human keratinocytes were immortalized by long-term expression of HPV type 16 E6 or E7 oncoproteins, or both. Proteomic profiling was used to compare expression levels for 741 discrete protein features. Results Six replicate measurements were performed for each group using two-dimensional difference gel electrophoresis (2D-DIGE). The median within-group coefficient of variation was 19–21%. Significance of between-group differences was tested based on Significance Analysis of Microarray and fold change. Expression of 170 (23%) of the protein features changed significantly in immortalized cells compared to primary keratinocytes. Most of these changes were qualitatively similar in cells immortalized by E6, E7, or E6/7 expression, indicating convergence on a common phenotype, but fifteen proteins (~2%) were outliers in this regulatory pattern. Ten demonstrated opposite regulation in E6- and E7-expressing cells, including the cell cycle regulator p16INK4a; the carbohydrate binding protein Galectin-7; two differentially migrating forms of the intermediate filament protein Cytokeratin-7; HSPA1A (Hsp70-1); and five unidentified proteins. Five others had a pattern of expression that suggested cooperativity between the co-expressed oncoproteins. Two of these were identified as forms of the small heat shock protein HSPB1 (Hsp27). Conclusion This large-scale analysis provides a framework for understanding the cooperation between E6 and E7 oncoproteins in HPV-driven carcinogenesis.

Abstract Background During the last decade, the use of microarrays to assess the transcriptome of many biological systems has generated an enormous amount of data. A common technique used to organize and analyze microarray data is to perform cluster analysis. While many clustering algorithms have been developed, they all suffer a significant decrease in computational performance as the size of the dataset being analyzed becomes very large. For example, clustering 10000 genes from an experiment containing 200 microarrays can be quite time consuming and challenging on a desktop PC. One solution to the scalability problem of clustering algorithms is to distribute or parallelize the algorithm across multiple computers. Results The software described in this paper is a high performance multithreaded application that implements a parallelized version of the K-means Clustering algorithm. Most parallel processing applications are not accessible to the general public and require specialized software libraries (e.g. MPI) and specialized hardware configurations. The parallel nature of the application comes from the use of a web service to perform the distance calculations and cluster assignments. Here we show our parallel implementation provides significant performance gains over a wide range of datasets using as little as seven nodes. The software was written in C# and was designed in a modular fashion to provide both deployment flexibility as well as flexibility in the user interface. Conclusion ParaKMeans was designed to provide the general scientific community with an easy and manageable client-server application that can be installed on a wide variety of Windows operating systems.

Presents a correction to the article "A Functional Variant of SUMO4, a New lκB&agr; Modifier, is Associated With Type 1 Diabetes," that was previously published in the 2004 issue of "Nature Genetics."

Alternaria dauci and Cercospora carotae cause foliar blight on carrot and can reduce yield in severely blighted fields. Historically, fungicides are applied every 7 to 14 days even though applications may be made when environmental conditions do not favor blight development. The purpose of this study was to compare a calendar-based application schedule with three disease forecasting systems for timing fungicide sprays to limit foliar blight, and included (i) an A. dauci disease forecaster, (ii) TOM-CAST, using a threshold of 15 disease severity values, and (iii) a disease forecaster developed to control C. apii on celery. Chlorothalonil was applied weekly or according to the forecasting systems to blight-susceptible ‘Cellobunch’ carrot plants in 2001 and 2002. Overall petiole health was poor (≥8.3; 10 = 100% petiole necrosis) when fungicides were not used. Although all disease forecasters maintained petiole health (≤5.3; 1 = healthy and vigorous), the TOM-CAST program had the best petiole health rating each year (≤2.8). TOM-CAST prompted 38 to 54% fewer applications than the weekly application schedule, resulting in a fungicide savings of $105 and $147/ha in 2001 and 2002, respectively, while providing similar blight control. The number of sprays also was reduced when fungicides were applied according to the A. dauci and C. apii forecasters, but acceptable blight control was not always achieved. [ABSTRACT FROM AUTHOR]

Background: Anaphylaxis is a serious allergic reaction that is rapid in onset and may cause death. To date, there are no published data on epidemiology of pediatric anaphylaxis in Michigan. Our objective was to describe and compare the time trends in incidence of anaphylaxis in urban and suburban populations of Metro Detroit., Methods: We performed a retrospective study of Pediatric Emergency Department (ED) anaphylaxis visits from January 1, 2010, to December 1, 2017. The study was conducted at 1 suburban ED (SED) and 1 urban ED (UED). We identified cases using an International Classification of Diseases (ICD) 9 and 10 query of the electronic medical record. Patients were included if they aged 0-17 years and met the 2006 National Institute of Allergy and Infectious Disease and the Food Allergy and Anaphylaxis Network diagnostic criteria for anaphylaxis. The anaphylaxis rate was calculated as the number of detected cases divided by the total number of pediatric emergency room visits for that month. Anaphylaxis rates were compared between the two EDs using Poisson regression., Results: A total of 8,627 patient encounters had ICD codes for anaphylaxis, of which 703 visits fulfilled the inclusion criteria and were used in subsequent analyses. Overall, the incidence of anaphylaxis was more common in males and in children < 4 years of age in both centers. Although the total number of anaphylaxis related visits was higher at UED over the eight-year time frame for this study, the anaphylaxis rate (cases per 100,000 ED visits) throughout the study was higher at the SED. While the observed anaphylaxis rate at UED was 10.47 - 162.05 cases per 100,000 ED visits, the observed anaphylaxis rate at SED was 0 - 556.24 cases per 100,000 ED visits., Conclusion: Pediatric anaphylaxis rates differ significantly between urban and suburban populations in metro Detroit EDs. The rate of anaphylaxis related visits to the ED has significantly increased over the past 8 years in the metro Detroit area, with significantly higher rise in suburban compared to urban ED. More studies are needed to explore the reasons for this observed difference in increase rates., (© 2023. The Author(s).)

Background/aims: There is a close link between iron and polyamine biosynthesis and metabolism. In a recent study, we reported alterations in the serum levels of hepcidin and other iron-related proteins in Alzheimer's disease (AD) patients (Sternberg et al., 2017). Based on these findings, this pilot study compared serum levels of one of the polyamines, Spermidine, between AD, mild cognitive impairment (MCI), and control subjects, correlating the levels with the existing clinical and neuroimaging data., Methods: This cross-sectional study measured Spermidine levels in frozen serum samples of 43 AD patients, 12 MCI patients, and 21 age-matched controls, provided by the Oregon Alzheimer's Disease Center Bio-repository, using enzyme-linked immunosorbent assay., Results: MCI patients showed significantly higher mean Spermidine serum levels compared to controls (P = 0.01), with a non-significant trend for higher Spermidine serum levels in pure AD (P = 0.08) participants compared to controls. Spermidine serum levels correlated with the values of cognitive assessment tests including MMSE (r = -0.705, P = 0.003), CDR (r = 0.751, P = 0.002), and CDR-SOB (r = 0.704, P = 0.007), in "pure" AD subgroup, suggesting that higher Spermidine serum levels in MCI can be a potential biomarker of conversion to dementia in subjects with AD underlying pathology. Furthermore, Spermidine serum levels correlated with serum levels of the chief iron regulatory protein, hepcidin in AD participants with a more advanced disease stage, indicated by MMSE (strata of 8-19, P = 0.02), and CDR-SOB (strata of 6-12, P = 0.03)., Conclusion: Studies with larger cohort are warranted for defining the role of Spermidine in AD pathophysiology, and the utility of polyamines as biomarkers of progression of MCI to AD., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background . Lung compliance (LC) is the ability of the lung to expand with changes in pressure and is one of the earliest physiological measurements to be altered in patients with parenchymal lung disease. Therefore, compliance monitoring could potentially identify patients at risk for disease progression. However, in clinical practice, compliance measurements are prohibitively invasive for use as a routine monitoring tool. Purpose . We propose a novel method for computing dynamic lung compliance imaging (LCI) from non-contrast computed tomography (CT) scans. LCI applies image processing methods to free-breathing 4DCT images, acquired under two different continuous positive airway pressures (CPAP) applied using a full-face mask, in order to compute the lung volume change induced by the pressure change. LCI provides a quantitative volumetric map of lung stiffness. Methods . We compared mean LCI values computed for 10 patients with idiopathic pulmonary fibrosis (IPF) and 7 non-IPF patients who were screened for lung nodules. 4DCTs were acquired for each patient at 5 cm and 10 cm H 2 0 CPAP, as the patients were free breathing at functional residual capacity. LCI was computed from the two 4DCTs. Mean LCI intensities, which represent relative voxel volume change induced by the change in CPAP pressure, were computed. Results. The mean LCI values for patients with IPF ranged between [0.0309, 0.1165], whereas the values ranged between [0.0704, 0.2185] for the lung nodule cohort. Two-sided Wilcoxon rank sum test indicated that the difference in medians is statistically significant ( p value = 0.009) and that LCI -measured compliance is overall lower in the IPF patient cohort. Conclusion . There is considerable difference in LC scores between patients with IPF compared to controls. Future longitudinal studies should look for LC alterations in areas of lung prior to radiographic detection of fibrosis to further characterize LCI's potential utility as an image marker for disease progression., (© 2021 Institute of Physics and Engineering in Medicine.)

Purpose: Limited diagnostic options exist for patients with suspected pulmonary embolism (PE) who cannot undergo CT-angiogram (CTA). CT-ventilation methods recover respiratory motion-induced lung volume changes as a surrogate for ventilation. We recently demonstrated that pulmonary blood mass change, induced by tidal respiratory motion, is a potential surrogate for pulmonary perfusion. In this study, we examine blood mass and volume change in patients with PE and parenchymal lung abnormalities (PLA)., Methods: A cross-sectional analysis was conducted on a prospective, cohort-study with 129 consecutive PE suspected patients. Patients received 4DCT within 48 h of CTA and were classified as having PLA and/or PE. Global volume change (VC) and percent global pulmonary blood mass change (PBM) were calculated for each patient. Associations with disease type were evaluated using quantile regression., Results: 68 of 129 patients were PE positive on CTA. Median change in PBM for PE-positive patients (0.056; 95% CI: 0.045, 0.068; IQR: 0.051) was smaller than that of PE-negative patients (0.077; 95% CI: 0.064, 0.089; IQR: 0.056), with an estimated difference of 0.021 (95% CI: 0.003, 0.038; p = 0.0190). PLA was detected in 57 (44.2%) patients. Median VC for PLA-positive patients (1.26; 95% CI: 1.22, 1.30; IQR: 0.15) showed no significant difference from PLA-negative VC (1.25; 95% CI: 1.21, 1.28; IQR: 0.15)., Conclusions: We demonstrate that pulmonary blood mass change is significantly lower in PE-positive patients compared to PE-negative patients, indicating that PBM derived from dynamic non-contrast CT is a potentially useful surrogate for pulmonary perfusion., (Copyright © 2021. Published by Elsevier Inc.)

Objective: To evaluate CT-ventilation imaging (CTVI) within a well-characterized, healthy cohort with no respiratory symptoms and examine the correlation between CTVI and concurrent pulmonary function test (PFT)., Methods: CT scans and PFTs from 77 Caucasian participants in the NORM dataset (clinicaltrials.gov NCT00848406) were analyzed. CTVI was generated using the robust Integrated Jacobian Formulation (IJF) method. IJF estimated total lung capacity (TLC) was computed from CTVI. Bias-adjusted Pearson's correlation between PFT and IJF-based TLC was computed., Results: IJF- and PFT-measured TLC showed a good correlation for both males and females [males: 0.657, 95% CI (0.438-0.797); females: 0.667, 95% CI (0.416-0.817)]. When adjusting for age, height, smoking, and abnormal CT scan, correlation moderated [males: 0.432, 95% CI (0.129-0.655); females: 0.540, 95% CI (0.207-0.753)]. Visual inspection of CTVI revealed participants who had functional defects, despite the fact that all participant had normal high-resolution CT scan., Conclusion: In this study, we demonstrate that IJF computed CTVI has good correlation with concurrent PFT in a well-validated patient cohort with no respiratory symptoms., Advances in Knowledge: IJF-computed CTVI's overall numerical robustness and consistency with PFT support its potential as a method for providing spatiotemporal assessment of high and low function areas on volumetric non-contrast CT scan.

Background/aims: Prostate specific antigen (PSA) is regulated by steroid hormones, such as testosterone, the serum levels of which are altered in patients with Alzheimer's disease (AD).This pilot study compared serum levels of the free (f) PSA between AD, mild cognitive impairment (MCI), and control subjects, and evaluated the relationship between fPSA serum levels and cognitive assessment tests and neuroimaging data. In addition, in a subgroup of AD patients, we correlated fPSA serum levels with the existing data on serum levels of amyloid-beta (Aβ), and iron-related proteins, including hepcidin and ferritin., Methods: Frozen serum samples from the Oregon Tissue Bank were used to measure serum levels of fPSA using enzyme-linked immunosorbent assay., Results: fPSA serum levels calculated as median ± SD were higher in AD males (663.6 ± 821.0 pg/ml) compared to control males (152.0 ± 207.0 pg/ml), p = 0.003. A similar Pattern emerged when comparing MCI males (310.7 ± 367.0 pg/ml) to control males (P = 0.02). Correlation studies showed a significant association between fPSA and CDR (r = 0.56, P = 0.006) and CDR-SOB (r = 0.54, P = 0.009) in AD males., Conclusion: Additional studies in a larger cohort are required for determining whether fPSA can be used as biomarker of AD disease progression and whether it has the potential to identify male subjects at risk of AD dementia., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Plantar fasciitis is considered the most common cause of foot pain. Numerous non-surgical treatments have been used to relieve symptoms. Taping is one of the most widespread treatments, with several techniques utilized in clinical practice., Objective: To evaluate, based on existing literature, the efficacy of different taping techniques in relieving symptoms and dysfunction caused by plantar fasciitis., Methods: PubMed, CINAHL, PEDro, ISIWeb of Science, and Google Scholar databases were searched from inception until December 2012, using a predefined search strategy. Controlled trials of any methodological quality were included, without any language restrictions. The methodological quality of interventional studies was evaluated inter alia by the PEDro score., Results: Five randomized control trials, one cross-over study and two single group repeated measures studies met the inclusion criteria. Two studies were high quality; two were moderate quality and four were of poor methodological quality. All eight studies favored the use of different taping techniques. The most common technique was low dye taping., Conclusion: We found that in the short-term, taping is beneficial in treating plantar fasciitis. The best evidence exists for low dye taping and calcaneal taping. More research is needed to investigate long-term effect and effectiveness of specific taping techniques.

We have previously shown that liposomes composed of egg-derived phosphatidylglycerol (PG), with a mixed fatty acid composition (comprising mainly palmitate and oleate), inhibit the proliferation and promote the differentiation of rapidly dividing keratinocytes, and stimulate the growth of slowly proliferating epidermal cells. To determine the species of PG most effective at modulating keratinocyte proliferation, primary mouse keratinocytes were treated with different PG species, and proliferation was measured. PG species containing polyunsaturated fatty acids were effective at inhibiting rapidly proliferating keratinocytes, whereas PG species with monounsaturated fatty acids were effective at promoting proliferation in slowly dividing cells. Thus, palmitoyl-arachidonyl-PG (16∶0/20∶4), palmitoyl-linoleoyl-PG (16∶0/18∶2), dilinoleoyl-PG (18∶2/18∶2) and soy PG (a PG mixture with a large percentage of polyunsaturated fatty acids) were particularly effective at inhibiting proliferation in rapidly dividing keratinocytes. Conversely, palmitoyl-oleoyl-PG (16∶0/18∶1) and dioleoyl-PG (18∶1/18∶1) were especially effective proproliferative PG species. This result represents the first demonstration of opposite effects of different species of a single class of phospholipid and suggests that these different PG species may signal to diverse effector enzymes to differentially affect keratinocyte proliferation and normalize keratinocyte proliferation. Thus, different PG species may be useful for treating skin diseases characterized by excessive or insufficient proliferation.

Background: Indoleamine 2,3 dioxygenase (IDO) degrades the essential amino acid tryptophan and has been shown to minimize rejection in animal models of renal transplantation. Ischemia-reperfusion injury (IRI) is unavoidable in renal transplantation and correlates with shorter graft survival times. Despite its favorable effects on rejection, there is evidence that IDO may facilitate renal IRI. Differentiating the negative impact of IDO on IRI from its pro-tolerant effects in allograft rejection is of clinical relevance. In these studies we hypothesized that constitutive IDO activity may influence renal genes associated with recovery from IRI, and that IDO inhibition may unmask these effects., Methods: We examined the renal transcriptome in a rat model of IRI with and without IDO inhibition with 1-methyl-d-tryptophan (1-MT), and assessed for alterations in the gene expression signature., Results: These studies demonstrated that during recovery from renal IRI, pre-treatment with 1-MT alleviated alterations in 105 coding sequences associated with IRI, and in turn triggered new changes in 66 non-coding transcripts, the majority of which were represented by small nucleolar RNA., Conclusion: These results suggest a biologic role for non-coding, IDO-dependent genes in regulating the early response to IRI., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Objective: To survey a cross-section of reproductive-age Salvadoran women in order to assess the factors that influence their decision to use depot-medroxyprogesterone acetate (DMPA), an injectable form of contraception., Methods: Reproductive-age women at three rural Salvadoran health clinics were asked to participate in a study to assess their current and past experiences using DMPA contraception. Verbal informed consent was obtained, and research coordinators administered a 23-question survey., Results: Surveys were completed in 425 women with an average age of 27.36 years. Average duration of DMPA contraception use was 2.89 years. The majority (84%) of past and present users were very satisfied with DMPA contraception, most commonly because they did not have to remember to use it daily (44.9%). The side effects of DMPA appear to be a significant indicator of whether women heard about and wanted to use other forms of long-term reversible contraception, such as an intrauterine device (IUD) or implant., Conclusions: The main reason Salvadoran women chose to use DMPA is because they do not have to think about it on a daily basis. However, many women do not like the side effects and may be open to explore using other long-term reversible methods of contraception, such as IUDs or implants. It is possible that with increased access to educational information about IUD use, safety, and effectiveness, more women would use this form of long-term contraception as opposed to sterilization.

Purpose: After uniocular anterior chamber (AC) injection of HSV-1, the anterior segment of BALB/c mice becomes inflamed and infected; however, virus does not spread from the anterior segment to cause retinitis in the injected eye. The purpose of these studies was to determine whether interferon (IFN-)-γ and Mac-1(+) cells play a role in preventing direct anterior-to-posterior spread of HSV-1 in the injected eye., Methods: One AC of adult female BALB/c mice was injected with HSV-1 (KOS). The location of IFN-α, IFN-β, and IFN-γ in the injected eye was determined by immunofluorescence, and mRNA expression was quantified by qPCR. Injected eyes of IFN-γ knockout or clodronate-treated macrophage-depleted mice were examined to determine whether the absence of IFN-γ or Mac-1(+) macrophages affected the sites or timing of virus spread., Results: IFN-α, IFN-β, and IFN-γ were observed in the anterior segment of injected eyes through 72 hours and mRNA levels of IFN-β and IFN-γ were increased in virus-infected eyes 48 to 120 hours after infection. However, the absence of IFN-γ or macrophages did not affect either the sites or the timing of HSV-1 infection in injected eyes., Conclusions: Protection of the retina of the injected eye does not depend on a single cell type or cytokine. In addition, in the eye, as in other sites of the body, there are redundancies in the innate response to virus infection.

Disordered angiogenesis is implicated in pulmonary vascular remodeling secondary to congenital heart diseases (CHD). However, the underlying genes are not well delineated. We showed previously that an ovine model of CHD with increased pulmonary blood flow (PBF, Shunt) has an "angiogenesis burst" between 1 and 4 wk of age. Thus we hypothesized that the increased PBF elicited a proangiogenic gene expression profile before onset of vessel growth. To test this we utilized microarray analysis to identify genes that could be responsible for the angiogenic response. Total RNA was isolated from lungs of Shunt and control lambs at 3 days of age and hybridized to Affymetrix gene chips for microarray analyses (n = 8/group). Eighty-nine angiogenesis-related genes were found to be upregulated and 26 angiogenesis-related genes downregulated in Shunt compared with control lungs (cutting at 1.2-fold difference, P < 0.05). We then confirmed upregulation of proangiogenic genes FGF2, Angiopoietin2 (Angpt2), and Birc5 at mRNA and protein levels and upregulation of ccl2 at mRNA level in 3-day Shunt lungs. Furthermore, we found that pulmonary arterial endothelial cells (PAEC) isolated from fetal lambs exhibited increased expression of FGF2, Angpt2, Birc5, and ccl2 and enhanced angiogenesis when exposed to elevated shear stress (35 dyn/cm²) compared with cells exposed to more physiological shear stress (20 dyn/cm²). Finally, we demonstrated that blocking FGF2, Angpt2, Birc5, or ccl2 signaling with neutralizing antibodies or small interfering RNA (siRNA) significantly decreased the angiogenic response induced by shear stress. In conclusion, we have identified a "proangiogenic" gene expression profile in a lamb model of CHD with increased PBF that precedes onset of pulmonary vascular remodeling. Our data indicate that FGF2, Angpt2, Birc5, and ccl2 may play important roles in the angiogenic response.

Type 1 diabetes (T1D) is an autoimmune disease resulting from the complex interaction between multiple susceptibility genes, environmental factors and the immune system. Over 40 T1D susceptibility regions have been suggested by recent genome-wide association studies; however, the specific genes and their role in the disease remain elusive. The objective of this study is to identify the susceptibility gene(s) in the 12q13 region and investigate the functional link to the disease pathogenesis. A total of 19 SNPs in the 12q13 region were analyzed by the TaqMan assay for 1,434 T1D patients and 1,865 controls. Thirteen of the SNPs are associated with T1D (best p = 4x10(-11)), thus providing confirmatory evidence for at least one susceptibility gene in this region. To identify candidate genes, expression of six genes in the region was analyzed by real-time RT-PCR for PBMCs from 192 T1D patients and 192 controls. SNP genotypes in the 12q13 region are the main factors that determine ERBB3 mRNA levels in PBMCs. The protective genotypes for T1D are associated with higher ERBB3 mRNA level (p<10(-10)). Furthermore, ERBB3 protein is expressed on the surface of CD11c(+) cells (dendritic cells and monocytes) in peripheral blood after stimulation with LPS, polyI:C or CpG. Subjects with protective genotypes have significantly higher percentages of ERBB3(+) monocytes and dendritic cells (p = 1.1x10(-9)); and the percentages of ERBB3(+) cells positively correlate with the ability of APC to stimulate T cell proliferation (R(2) = 0.90, p<0.0001). Our results indicate that ERBB3 plays a critical role in determining APC function and potentially T1D pathogenesis.

Motivation: Significance analysis of microarrays (SAM) is a widely used permutation-based approach to identifying differentially expressed genes in microarray datasets. While SAM is freely available as an Excel plug-in and as an R-package, analyses are often limited for large datasets due to very high memory requirements., Summary: We have developed a parallelized version of the SAM algorithm called ParaSAM to overcome the memory limitations. This high performance multithreaded application provides the scientific community with an easy and manageable client-server Windows application with graphical user interface and does not require programming experience to run. The parallel nature of the application comes from the use of web services to perform the permutations. Our results indicate that ParaSAM is not only faster than the serial version, but also can analyze extremely large datasets that cannot be performed using existing implementations., Availability: A web version open to the public is available at http://bioanalysis.genomics.mcg.edu/parasam. For local installations, both the windows and web implementations of ParaSAM are available for free at http://www.amdcc.org/bioinformatics/software/parasam.aspx.

Peroxisome proliferator-activated receptor type gamma (PPARgamma) is a subgroup of the PPAR transcription factor family. Recent studies indicate that loss of PPARgamma is associated with the development of pulmonary hypertension (PH). We hypothesized that the endothelial dysfunction associated with PPARgamma inhibition may play an important role in the disease process by altering cellular gene expression and signaling cascades. We utilized microarray analysis to determine if PPARgamma inhibition induced changes in gene expression in pulmonary arterial endothelial cells (PAEC). We identified 100 genes and expressed sequence tags (ESTs) that were upregulated by >1.5-fold and 21 genes and ESTs that were downregulated by >1.3-fold (P < 0.05) by PPARgamma inhibition. The upregulated genes can be broadly classified into four functional groups: cell cycle, angiogenesis, ubiquitin system, and zinc finger proteins. The genes with the highest fold change in expression: hyaluronan-mediated motility receptor (HMMR), VEGF receptor 2 (Flk-1), endothelial PAS domain protein 1 (EPAS1), basic fibroblast growth factor (FGF-2), and caveolin-1 in PAEC were validated by real time RT-PCR. We further validated the upregulation of HMMR, Flk-1, FGF2, and caveolin-1 by Western blot analysis. In keeping with the microarray results, PPARgamma inhibition led to re-entry of cell cycle at G(1)/S phase and cyclin C upregulation. PPARgamma inhibition also exacerbated VEGF-induced endothelial barrier disruption. Finally we confirmed the downregulation of PPARgamma and the upregulation of HMMR, Flk-1, FGF2, and Cav-1 proteins in the peripheral lung tissues of an ovine model of PH. In conclusion, we have identified an array of endothelial genes modulated by attenuated PPARgamma signaling that may play important roles in the development of PH.