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Abstract Background Network Component Analysis (NCA) has been used to deduce the activities of transcription factors (TFs) from gene expression data and the TF-gene binding relationship. However, the TF-gene interaction varies in different environmental conditions and tissues, but such information is rarely available and cannot be predicted simply by motif analysis. Thus, it is beneficial to identify key TF-gene interactions under the experimental condition based on transcriptome data. Such information would be useful in identifying key regulatory pathways and gene markers of TFs in further studies. Results We developed an algorithm to trim network connectivity such that the important regulatory interactions between the TFs and the genes were retained and the regulatory signals were deduced. Theoretical studies demonstrated that the regulatory signals were accurately reconstructed even in the case where only three independent transcriptome datasets were available. At least 80% of the main target genes were correctly predicted in the extreme condition of high noise level and small number of datasets. Our algorithm was tested with transcriptome data taken from mice under rapamycin treatment. The initial network topology from the literature contains 70 TFs, 778 genes, and 1423 edges between the TFs and genes. Our method retained 1074 edges (i.e. 75% of the original edge number) and identified 17 TFs as being significantly perturbed under the experimental condition. Twelve of these TFs are involved in MAPK signaling or myeloid leukemia pathways defined in the KEGG database, or are known to physically interact with each other. Additionally, four of these TFs, which are Hif1a, Cebpb, Nfkb1, and Atf1, are known targets of rapamycin. Furthermore, the trimmed network was able to predict Eno1 as an important target of Hif1a; this key interaction could not be detected without trimming the regulatory network. Conclusions The advantage of our new algorithm, relative to the original NCA, is that our algorithm can identify the important TF-gene interactions. Identifying the important TF-gene interactions is crucial for understanding the roles of pleiotropic global regulators, such as p53. Also, our algorithm has been developed to overcome NCA's inability to analyze large networks where multiple TFs regulate a single gene. Thus, our algorithm extends the applicability of NCA to the realm of mammalian regulatory network analysis.

Abstract Background Ischemic stroke is the most common cause of disability in North America and in addition to the generally accepted risk factors, there is increasing evidence for the potential pathophysiological role of genes. One of these genes, the endothelial nitric oxide synthase gene (NOS3) has been reported as a genetic risk factor for ischemic stroke. To independently confirm and extend the results of these previous reports, we investigated this gene as a risk factor for stroke in an ethnically diverse study population. Methods Using the TOAST classification, we characterized and studied 377 patients with ischemic stroke. We genotyped two common variants in the NOS3 gene, the intron 4 insertion/deletion and an exonic single nucleotide polymorphism (SNP), G894T, in these patients and compared them with 502 controls. Chi-square or Fisher's exact tests were used to examine allele effects on stroke and stroke subtypes. Logistic regression analysis was used to adjust for confounding covariate effects. Results All genotypes are in Hardy-Weinberg equilibrium except for intron 4c, which is overrepresented in ischemic stroke patients. In pooled analysis of all patients, intron 4c, but not intron 4a, intron 4b or G894T alleles are associated with stroke (p < 0.01). In subgroup analysis by race, the intron 4c allele is most strongly associated with large artery ischemic stroke in African Americans (p < 0.01). Conclusion We are unable to confirm previous reports of an association of the intron 4a or the G894T alleles with ischemic stroke. However, although limited by a relatively small sample size, our study suggests a potentially important role of the intron 4c allele as a genetic marker of ischemic stroke in African Americans.

Abstract Background Since transcription factors are often regulated at the post-transcriptional level, their activities, rather than expression levels may provide valuable information for investigating functions and their interactions. The recently developed Network Component Analysis (NCA) and its generalized form (gNCA) provide a robust framework for deducing the transcription factor activities (TFAs) from various types of DNA microarray data and transcription factor-gene connectivity. The goal of this work is to demonstrate the utility of TFAs in inferring transcription factor functions and interactions in Saccharomyces cerevisiae cell cycle regulation. Results Using gNCA, we determined 74 TFAs from both wild type and fkh1 fkh2 deletion mutant microarray data encompassing 1529 ORFs. We hypothesized that transcription factors participating in the cell cycle regulation exhibit cyclic activity profiles. This hypothesis was supported by the TFA profiles of known cell cycle factors and was used as a basis to uncover other potential cell cycle factors. By combining the results from both cluster analysis and periodicity analysis, we recovered nearly 90% of the known cell cycle regulators, and identified 5 putative cell cycle-related transcription factors (Dal81, Hap2, Hir2, Mss11, and Rlm1). In addition, by analyzing expression data from transcription factor knockout strains, we determined 3 verified (Ace2, Ndd1, and Swi5) and 4 putative interaction partners (Cha4, Hap2, Fhl1, and Rts2) of the forkhead transcription factors. Sensitivity of TFAs to connectivity errors was determined to provide confidence level of these predictions. Conclusion By subjecting TFA profiles to analyses based upon physiological signatures we were able to identify cell cycle related transcription factors consistent with current literature, transcription factors with potential cell cycle dependent roles, and interactions between transcription factors.

The problems and successes of a community immunization program for childhood diseases are described. (JD)

Abstract The Indian Shield is cross-cut by a number of distinct Paleoproterozoic mafic dyke swarms. The density of dykes in the Dharwar and Bastar Cratons is amongst the highest on Earth. Globally, boninitic dyke swarms are rare compared to tholeiitic dyke swarms and yet they are common within the Southern Indian Shield. Geochronology and geochemistry are used to constrain the petrogenesis and relationship of the boninitic dykes (SiO 2 = 51.5 to 55.7 wt%, MgO = 5.8 to 18.7 wt%, and TiO 2 = 0.30 wt% to 0.77 wt%) from the central Bastar Craton (Bhanupratappur) and the NE Dharwar Craton (Karimnagar). A single U-Pb baddeleyite age from a boninitic dyke near Bhanupratappur yielded a weighted-mean 207Pb/206Pb age of 2365.6 ± 0.9 Ma that is within error of boninitic dykes from the Dharwar Craton near Karimnagar (2368.5 ± 2.6 Ma) and farther south near Bangalore (2365.4 ± 1.0 Ma to 2368.6 ± 1.3 Ma). Rhyolite-MELTS modeling indicates that fractional crystallization is the likely cause of major element variability of the boninitic dykes from Bhanupratappur whereas trace element modeling indicates that the primary melt may be derived from a pyroxenite mantle source near the spinel-garnet transition zone. The Nd isotopes (ε Nd (t) = −6.4 to +4.5) of the Bhanupratappur dykes are more variable than the Karimnagar dykes (ε Nd (t) = −0.7 to +0.6) but they overlap. The variability of Sr-Nd isotopes may be related to crustal contamination during emplacement or is indicative of an isotopically heterogeneous mantle source. The chemical and temporal similarities of the Bhanupratappur dykes with the dykes of the Dharwar Craton (Karimnagar, Penukonda, Chennekottapalle) indicate they are members of the same giant radiating dyke swarm. Moreover, our results suggest that the Bastar and Dharwar Cratons were adjacent but likely had a different configuration at 2.37 Ga than the present day. It is possible that the 2.37Ga dyke swarm was related to a mantle plume that assisted in the break-up of an unknown or poorly constrained supercontinent. Graphical abstract Unlabelled Image Highlights • NW-SE trending boninitic mafic dykes of the central Bastar Craton are 2365.6 ± 0.9 Ma. • Dyke chemical variability is related to crystal fractionation and contamination. • The primary magmas were likely derived from a spinel-bearing pyroxenite source. • Dyke correlation indicates the Dharwar and Bastar Cratons were connected at 2.37 Ga. [ABSTRACT FROM AUTHOR]

A nanotube assisted microwave electroporation (NAME) technique is demonstrated for delivering molecular biosensors into viable bacteria for multiplex single cell pathogen identification to advance rapid diagnostics in clinical microbiology. Due to the small volume of a bacterial cell (~femtoliter), the intracellular concentration of the target molecule is high, which results in a strong signal for single cell detection without amplification. The NAME procedure can be completed in as little as 30 minutes and can achieve over 90% transformation efficiency. We demonstrate the feasibility of NAME for identifying clinical isolates of bloodborne and uropathogenic pathogens and detecting bacterial pathogens directly from patient's samples. In conjunction with a microfluidic single cell trapping technique, NAME allows single cell pathogen identification and antimicrobial susceptibility testing concurrently. Using this approach, the time for microbiological analysis reduces from days to hours, which will have a significant impact on the clinical management of bacterial infections. A nanotube assisted microwave electroporation (NAME) technique is demonstrated for rapid microbiological analysis of pathogenic bacteria. NAME delivers molecular biosensors into viable bacteria for multiplex single cell pathogen identification and antimicrobial susceptibility testing. The technique determines the species in as little as 30 minutes and perform antimicrobial susceptibility testing in less than 3 hours. Unlabelled Image [ABSTRACT FROM AUTHOR]

The optical absorption of synthetic ReS[sub 2] and ReSe[sub 2] single crystals is reported over a temperature range from 25 to 300 K. Analysis reveals that the absorption edges of ReS[sub 2] and ReSe[sub 2] are indirect allowed transitions. The indirect band gaps at various temperatures are determined and their temperature dependence is analyzed by the Varshni equation [Physica 34, 149 (1967)] and an empirical expression proposed by O'Donnel and Chen [Appl. Phys. Lett. 58, 2924 (1991)]. The parameters that describe the temperature dependence of energy gaps of these two materials are evaluated and discussed. [ABSTRACT FROM AUTHOR]

In real life, it is not always the case that experts are able to assess alternatives by precise values. With the incomplete and vague information obtained, the experts are inclined to provide their assessments by eliciting linguistic terms. Considering that the experts may hesitate between several linguistic terms during the evaluating process, a new tool called the hesitant fuzzy linguistic term set (HFLTS) was introduced to represent this situation. This tool allows the experts to use several possible linguistic terms rather than a single one to appraise the performances of alternatives. In this paper, we investigate the ELECTRE II method in the HFLTS environment and propose two new approaches named the score-deviation-based ELECTRE II method and the positive and negative ideal hesitant fuzzy linguistic elements based ELECTRE II method. To fully explore the underlying preference information and specify the outranking degrees of alternatives, we set up three levels of concordance and discordance sets, which are finally devoted to ranking the alternatives more convincingly. An illustrative example is operated to show the practicability of the proposed methods and then a sensitivity analysis is performed as well to test the robustness of the two methods. [ABSTRACT FROM AUTHOR]

Porous-asphalt concrete (PAC), with its large portion of void content, would result in an increased potential for accelerating aging. Rapid oxidation of the asphalt binder films has an adverse impact on the structural durability of PAC pavements. In addition, the use of fine-graded PAC is more desirable; they have a potential to be more economical because they can be placed in thinner layers. The aim of this work is to characterize the influence of aging on the engineering properties of fine-graded PACs. Test results show that aged PAC mixtures are found to have the better performance in tensile strength and rutting resistance compared to unaged PACs, but the aging has a detrimental influence on the raveling resistance and moisture susceptibility. The 4-day long-term aging procedure led to a considerable reduction in the tensile-strength ratio for PAC mixtures irrespective of binder type and gradation. In addition, the values of resilient modulus and tensile strength for the fine-graded PACs appeared to be higher than those for the coarser-graded PAC mixture. Based on the results obtained from the wheel track testing, the use of premium asphalt enhanced the cohesive strength and adhesion, thereby reducing the proportional rut depth of PAC. In terms of the overall performance evaluation, the fine-graded PAC with the highly modified asphalt binder can be used without compromising engineering properties. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate college-age women's knowledge of appropriate doses and potential toxicities of acetaminophen, competency in interpreting Drug Facts label dosing information, and ability to recognize products containing acetaminophen.Methods: In this cross-sectional prospective study, a 20-item written survey was provided to female college students at a University of Michigan fundraising event in March 2015.Results: A total of 203 female college students, 18-24 years of age, participated in the study. Pain was experienced on a daily or weekly basis by 22% of the subjects over the previous 6 months, and 83% reported taking acetaminophen. The maximum 3-gram daily dose of extra-strength acetaminophen was correctly identified by 64 participants; an additional 51 subjects indicated the generally accepted 4 grams daily as the maximum dose. When provided with the Tylenol Drug Facts label, 68.5% correctly identified the maximum amount of regular-strength acetaminophen recommended for a healthy adult. Hepatotoxicity was associated with high acetaminophen doses by 63.6% of participants, significantly more than those who selected distracter responses (P < 0.001). Knowledge of liver damage as a potential toxicity was correlated with age 20 years and older (P < 0.001) but was independent from race and ethnicity and level of alcohol consumption. Although more than one-half of the subjects (58.6%) recognized that Tylenol contained acetaminophen, fewer than one-fourth correctly identified other acetaminophen-containing products.Conclusion: Despite ongoing educational campaigns, a large proportion of the college-age women who participated in our study did not know and could not interpret the maximum recommended daily dose from Drug Facts labeling, did not know that liver damage was a potential toxicity of acetaminophen, and could not recognize acetaminophen-containing products. These data suggest a continued role for pharmacists in educational efforts targeted to college-age women. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To investigate the effect of autophagy on acute myocardial infarction (AMI), and its mechanism in rats. MATERIALS AND METHODS: A total of 75 Sprague Dawley (SD) rats were randomly divided into three groups (n=25): sham operation (S) group, the AMI group and rapamycin (RAPA) treatment group. The model of AMI was established and the myocardial infarction size was calculated by triphenyltetrazolium chloride (TTC) staining. Morphological changes in myocardium were observed by hematoxylin and eosin (HE) staining. Expression levels of autophagy-related proteins LC3-phosphatidylethanolamine conjugate (LC3-II) and p62 were detected by semi-quantitative polymerase chain reaction (PCR) and Western blot. RESULTS: Compared with the S group, the heart-to-body weight ratio on the 21st day in AMI group was significantly increased. TTC staining results showed that compared with the S group, the size of left ventricular infarction area was significantly increased in the AMI group, and that in the RAPA group was significantly decreased. HE staining results showed that the anterior wall of the left ventricle of rats became thinner, and myocardial cells were degenerated and lost seriously in the AMI group 21 days later. Compared with the S group, the expression level of LC3-II in the infarcted peripheral area was significantly increased and that of p62 was significantly increased in the AMI group. Compared with the AMI group, the expression level of LC3-II in the infarction-peripheral area was significantly increased and that of p62 was significantly decreased after the treatment with RAPA. CONCLUSIONS: Autologous activation could protect myocardium by the left anterior descending (LAD) ligation in rats. Autophagy could reduce the area of myocardial infarction after LAD ligation and improve cardiac function. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The involvement of microRNAs in cancer and their potential as biomarkers of prognosis are becoming increasingly appreciated. The aim of this study was to evaluate the clinical importance and prognostic value of miR- 342-3p in hepatocellular carcinoma (HCC). PATIENTS AND METHODS: RT-PCR was used to detect the expression of miR-342-3p. The association with clinicopathologic features was analyzed. Kaplan-Meier survival analysis and Cox proportional hazards analysis were used to compare the overall survival between HCC patients with high miR-342-3p expression and those with low miR-342-3p expression. RESULTS: We found that miR-342-3p expression was significantly decreased in HCC tissues compared with paired adjacent non-tumor tissues (p < 0.001). MiR-342-3p expression was correlated with histologic grade (p = 0.008) and tumor TNM stage (p = 0.001). Kaplan-Meier survival analysis showed that patients in the high miR-342-3p expression group had better overall survival than those in the low miR-342-3p expression group (p < 0.001). Univariate analysis showed that miR-342-3p (p = 0.001), TNM stage (p = 0.002) and histologic grade (p = 0.006) were associated with poor survival rates. Multivariate analysis confirmed that miR-342-3p expression can be used as an independent predictor for HCC prognosis (p = 0.002). CONCLUSIONS: miR-342-3p may serve as a tumor suppressor during HCC progression, and its low expression may be a potential biomarker for poor prognosis of HCC. [ABSTRACT FROM AUTHOR]

Summary: Direct-to-implant reconstruction after mastectomy is routinely performed with excellent oncologic and aesthetic outcomes. Several different techniques for placement of the prosthesis including total and partial subpectoral coverage have been described. Prepectoral implant placement is increasingly reported as a safe method, while patient selection and techniques are areas of further work. Most prepectoral prosthesis placement techniques describe complete acellular dermal matrix (ADM) coverage of the implant, often requiring multiple or larger ADM sheets than a comparable subpectoral implant procedure, resulting in high cost per reconstructed breast. This article describes the use of a vicryl mesh pocket and ADM support in prepectoral breast reconstruction achieving predicable and safe results at a lower cost.

Purpose Intraoperative optical biopsy technologies may aid in the identification of important anatomical landmarks and improve surgical outcomes of robotic assisted radical prostatectomy. We evaluate the feasibility of confocal laser endomicroscopy during robotic assisted radical prostatectomy. Materials and Methods A total of 21 patients with biopsy proven prostate cancer scheduled for robotic assisted radical prostatectomy were recruited. After intravenous administration of fluorescein 15 patients underwent in vivo intraoperative confocal laser endomicroscopy of prostatic and periprostatic structures using a 2.6 or 0.85 mm imaging probe. Standard robotic instruments were used to grasp and maneuver the confocal laser endomicroscopy probes for image acquisition. Confocal laser endomicroscopy imaging was performed ex vivo on fresh prostate specimens from 20 patients. Confocal video sequences acquired in vivo and ex vivo were reviewed and analyzed, with additional image processing using a mosaicing algorithm. Processed confocal images were compared with standard hematoxylin and eosin analysis of imaged regions. Results Confocal laser endomicroscopy was successfully integrated with robotic surgery, including co-registration of confocal video sequences with white light and probe handling with standard robotic instrumentation. Intraoperative confocal laser endomicroscopy imaging of the neurovascular bundle before and after nerve sparing dissection revealed characteristic features including dynamic vascular flow and intact axon fibers. Ex vivo confocal imaging of the prostatic parenchyma demonstrated normal prostate glands, stroma and prostatic carcinoma. Conclusions We report the initial feasibility of optical biopsy of prostatic and periprostatic tissue during robotic assisted radical prostatectomy. Image guidance and tissue interrogation using confocal laser endomicroscopy offer a new intraoperative imaging method that has the potential to improve the functional and oncologic outcomes of prostate cancer surgery. [ABSTRACT FROM AUTHOR]

Purpose The incidental detection of small renal masses is increasing. However, not all require aggressive treatments as up to 20% are benign and the majority of malignant tumors harbor indolent features. Improved preoperative diagnostics are needed to differentiate tumors requiring aggressive treatment from those more suitable for surveillance. We evaluated and compared confocal laser endomicroscopy with standard histopathology in ex vivo human kidney tumors as proof of principle towards diagnostic optical biopsy. Materials and Methods Patients with a solitary small renal mass scheduled for partial or radical nephrectomy were enrolled in study. Two kidneys were infused with fluorescein via intraoperative intravenous injection and 18 tumors were bathed ex vivo in dilute fluorescein prior to confocal imaging. A 2.6 mm confocal laser endomicroscopy probe was used to image tumors and surrounding parenchyma from external and en face surfaces after specimen bisection. Confocal laser endomicroscopy images were compared to standard hematoxylin and eosin analysis of corresponding areas. Results Ex vivo confocal laser endomicroscopy imaging revealed normal renal structures that correlated well with histology findings. Tumor tissue was readily distinguishable from normal parenchyma, demonstrating features unique to benign and malignant tumor subtypes. Topical fluorescein administration provided more consistent confocal laser endomicroscopy imaging than the intravenous route. Additionally, en face tumor imaging was superior to external imaging. Conclusions We report what is to our knowledge the first feasibility study using confocal laser endomicroscopy to evaluate small renal masses ex vivo and provide a preliminary atlas of images from various renal neoplasms with corresponding histology. These findings serve as an initial and promising step toward real-time diagnostic optical biopsy of small renal masses. [ABSTRACT FROM AUTHOR]