Genome-wide gene expression noise in Escherichia coli is condition-dependent and determined by propagation of noise through the regulatory network

Although it is well appreciated that gene expression is inherently noisy and that transcriptional noise is encoded in a promoter’s sequence, little is known about the extent to which noise levels of individual promoters vary across growth conditions. Using flow cytometry, we here quantify transcriptional noise in Escherichia coli genome-wide across 8 growth conditions and find that noise levels systematically decrease with growth rate, with a condition-dependent lower bound on noise. Whereas constitutive promoters consistently exhibit low noise in all conditions, regulated promoters are both more noisy on average and more variable in noise across conditions. Moreover, individual promoters show highly distinct variation in noise across conditions. We show that a simple model of noise propagation from regulators to their targets can explain a significant fraction of the variation in relative noise levels and identifies TFs that most contribute to both condition-specific and condition-independent noise propagation. In addition, analysis of the genome-wide correlation structure of various gene properties shows that gene regulation, expression noise, and noise plasticity are all positively correlated genome-wide and vary independently of variations in absolute expression, codon bias, and evolutionary rate. Together, our results show that while absolute expression noise tends to decrease with growth rate, relative noise levels of genes are highly condition-dependent and determined by the propagation of noise through the gene regulatory network.

Development of a microRNA Panel for Classification of Abnormal Mammograms for Breast Cancer

Mammography is extensively used for breast cancer screening but has high false-positive rates. Here, prospectively collected blood samples were used to identify circulating microRNA (miRNA) biomarkers to discriminate between malignant and benign breast lesions among women with abnormal mammograms. The Discovery cohort comprised 72 patients with breast cancer and 197 patients with benign breast lesions, while the Validation cohort had 73 and 196 cancer and benign cases, respectively. Absolute expression levels of 324 miRNAs were determined using RT-qPCR. miRNA biomarker panels were identified by: (1) determining differential expression between malignant and benign breast lesions, (2) focusing on top differentially expressed miRNAs, and (3) building panels from an unbiased search among all expressed miRNAs. Two-fold cross-validation incorporating a feature selection algorithm and logistic regression was performed. A six-miRNA biomarker panel identified by the third strategy, had an area under the curve (AUC) of 0.785 and 0.774 in the Discovery and Validation cohorts, respectively, and an AUC of 0.881 when differentiating between cases versus those with benign lesions or healthy individuals with normal mammograms. Biomarker panel scores increased with tumor size, stage and number of lymph nodes involved. Our work demonstrates that circulating miRNA signatures can potentially be used with mammography to differentiate between patients with malignant and benign breast lesions.

Buckwheat FeNramp5 mediates high Mn uptake in roots

Manganese (Mn) is an essential element for plant growth and development, but transporters required for Mn uptake have only been identified in a few plant species. Here, we functionally characterized a member of natural resistance-associated macrophage proteins (Nramps) family, FeNramp5 in buckwheat (Fagopyrum esculentum Moench), which is known as a species well adapted to acidic soils. FeNramp5 was mainly expressed in the roots and its expression was up-regulated by deficiency of Mn and Fe. Furthermore, spatial and tissue-specific expression analysis showed that FeNramp5 was expressed in all tissues of the basal root regions. FeNramp5-GFP protein was localized to the plasma membrane when transiently expressed in buckwheat leaf protoplast. FeNramp5 showed transport activity for Mn2+ and Cd2+, but not for Fe2+ when expressed in yeast. Furthermore, the transport activity for Mn2+ was higher in yeast expressing FeNramp5 than in yeast expressing AtNramp1. FeNramp5 was also able to complement phenotype of Arabidopsis atnramp1 mutant in terms of growth and accumulation of Mn and Cd. The absolute expression level of AtNramp1 was comparable to that of FeNramp5 in the roots, but buckwheat accumulated higher Mn than Arabidopsis when grown under the same condition. Further analysis showed that at least motif B in FeNramp5 seems important for its high transport activity for Mn. These results indicate that FeNramp5 is a transporter for uptake of Mn and Cd and its higher transport activity for Mn is probably associated with higher Mn accumulation in buckwheat.

Daphnia magna modifies its gene expression extensively in response to caloric restriction revealing a novel effect on haemoglobin isoform preference

Caloric restriction (CR) produces clear phenotypic effects within and between generations of the model crustacean Daphnia magna. We have previously established that micro RNAs and cytosine methylation change in response to CR in this organism, and we demonstrate here that CR has a dramatic effect on gene expression. Over 6000 genes were differentially expressed between CR and well-fed D. magna, with a bias towards up-regulation of genes under caloric restriction. We identified a highly expressed haemoglobin gene that responds to CR by changing isoform proportions. Specifically, a transcript containing three erythrocruorin domains was strongly down-regulated under CR in favour of transcripts containing fewer or no such domains. This change in the haemoglobin mix is similar to the response to hypoxia in Daphnia, which is mediated through the transcription factor hypoxia-inducible factor 1, and ultimately the mTOR signalling pathway. This is the first report of a role for haemoglobin in the response to CR. We also observed high absolute expression of super-oxide dismutase (SOD) in normally-fed individuals, which contrasts with observations of high SOD levels under in CR in other taxa. However, key differentially expressed genes, like SOD, were not targeted by differentially expressed micro-RNAs. Whether the link between Haemoglobin and CR is the case in other organisms, or is related to the aquatic lifestyle, remains to be tested. It suggests that one response to CR may be to simply transport less oxygen and lower respiration.

Plasma microRNA expression levels in HIV-1-positive patients receiving antiretroviral therapy

MicroRNAs (miRNAs/miRs) may serve as therapeutic agents or targets in diseases in which the expression of proteins plays an important role. The aim of the present study was to compare the expression levels of specific miRNAs, as well as their correlation with markers of response to antiretroviral (ARV) therapy, in patients with human immunodeficiency virus type 1 (HIV-1) infection with and without resistance to highly active antiretroviral therapy (HAART). Methods: miRNA assays were performed on plasma samples obtained from 20 HIV-1-positive patients. A total of ten patients were divided into two groups: HAART-responsive and HAART-resistant (n=5 per group). Commercial arrays were subsequently used to identify 84 miRNAs. A total of three differentially expressed miRNAs were selected and analyzed by quantitative PCR (qPCR). Five other patients were subsequently added to each group for a new relative expression analysis. The absolute expression level of the two miRNAs was obtained and compared using the Student’s t test. Receiver operating characteristic (ROC) curves were used to identify patients with antiretroviral therapy (ART) resistance. Results: The array analysis revealed that miR-15b-5p, miR-16-5p, miR-20a-5p, miR-26a-5p, miR-126-3p and miR-150-5p were down-regulated in patients with HAART-resistance comparing with HAART-responsive. The expression levels of miR-16-5p, miR-26a-5p and miR-150-5p were confirmed using qPCR. The area under the ROC curve was 1.0 for the three miRNAs. Conclusions: The lower expression levels of miR-16-5p and miR-26a-5p in patients with HAART-resistance suggested that these may serve as potential biomarkers for the identification of HAART-responsive patients.

Prediction of coronary disease incidence in the general population by circulating RNY(YRNA)-derived small RNA

ABSTRACTDuring the development of atherosclerotic lesion, s-RNYs (small RNAs of about 24/34 nucleotides) are derived by the processing of long Ro-associated non-coding RNAs (RNYs) in macrophages. The levels of serum s-RNYs have been found significantly upregulated in patients with coronary heart disease (CHD) compared to age-matched healthy individuals. The present study aimed to examine the predictive value of serum s-RNYs for CHD events in the general population.Within the frame of nested-case-control study, the GENES study, we measured the absolute expression of a RNY-derived small RNA, the s-RNY1-5p, in the serum of healthy individuals who encountered a CHD event within 12 years of follow-up (n = 31) (Cases) and compared them to individuals who remained event-free (Controls) (n = 30).The expression of s-RNY1-5p in serum was significantly upregulated in Cases compared to Controls (p = 0.027). The proportion of CHD event-free was significantly higher among individuals with serum s-RNY1-5p below the median value (631 molecule / mL). In a multivariate model adjusted for age, smoking and treatment for hypertension, diabetes and dyslipidemia, the risk of CHD events increased more than 4-fold in individuals with serum s-RNY1-5p above the median value (HR, 4.36; 95%CI, 1.22-15.60). Significant association with CHD events was also observed when considering s-RNY1-5p as a continuous variable (p = 0.022). Serum s-RNY1-5p is an independent predictor of CHD in healthy individuals and could be considered as a biomarker in primary prevention of cardiovascular diseases.TRANSLATIONAL PERSPECTIVESHere, we reported that s-RNY1-5p was significantly upregulated in the serum of individuals who underwent CHD and was positively associated with CHD events. Those results argue in favor of s-RNY1-5p being a novel predictive molecular biomarker for cardiovascular events. In the future, measurement of s-RNY1-5p expression levels and other 5’ s-RNYs, such as s-RNY4-5p, could be used in clinical practice in addition to classical risk factors to identify those high-risk individuals who might benefit from prevention medicine.

An absolute human stemness index associated with oncogenic dedifferentiation

The progression of cancer is accompanied by the acquisition of stemness features. Many stemness evaluation methods based on transcriptional profiles have been presented to reveal the relationship between stemness and cancer. However, instead of absolute stemness index values—the values with certain range—these methods gave the values without range, which makes them unable to intuitively evaluate the stemness. Besides, these indices were based on the absolute expression values of genes, which were found to be seriously influenced by batch effects and the composition of samples in the dataset. Recently, we have showed that the signatures based on the relative expression orderings (REOs) of gene pairs within a sample were highly robust against these factors, which makes that the REO-based signatures have been stably applied in the evaluations of the continuous scores with certain range. Here, we provided an absolute REO-based stemness index to evaluate the stemness. We found that this stemness index had higher correlation with the culture time of the differentiated stem cells than the previous stemness index. When applied to the cancer and normal tissue samples, the stemness index showed its significant difference between cancers and normal tissues and its ability to reveal the intratumor heterogeneity at stemness level. Importantly, higher stemness index was associated with poorer prognosis and greater oncogenic dedifferentiation reflected by histological grade. All results showed the capability of the REO-based stemness index to assist the assignment of tumor grade and its potential therapeutic and diagnostic implications.

Pengaruh Cuci Hidung dengan NaCl 0,9% Terhadap Ekspresi Gen IL-1Beta dan TNF-Alpha Mukosa Hidung Penderita Rinosinusitis Kronis di RSUP Dr M Djamil Padang

Chronic rhinosinusitis is an inflammatory disease of the nasal mucosa and paranasal sinuses which produces several proinflammatory cytokines including; IFN-γ, TGF-β1, IL-1β, IL-3, IL-6, IL-8, TNF-α, IL-5. The use of NaCl 0.9% nasal wash in chronic rhinosinusitis could reduce mucin secretion, decrease the production of postnasal drip, accelerate mucosal repair and reduce the symptoms of nasal obstruction. From above, researchers want to know the effect of NaCl 0.9% nasal wash of the levels of cytokines IL-1β and TNF-α in the mucosa of the nose and paranasal sinuses in patients with chronic rhinosinusitis. This research is an experimental study with the technique of pre and post test design to determine the effect of NaCl 0.9% nasal wash of the gene expression of IL-1β and TNF-α of nasal mucosa of patients with chronic rhinosinusitis. The amount of IL-1β gene copynumber before and after nasal wash is obtained 8.07 ± 0.95 and 8,20 ± 0.93 (p >0.05). The amount of TNF-α gene copynumber before and after nasal wash was 8,83 ±3,83 and 6,72 ±2,55 (p >0.05). IL-1β gene ratio starting and ending intervention in two groups was 52,51 ± 1.21 and 61,99 ± 1.13. TNF-α gene ratio starting and ending intervention in two groups was 9,63 ±2.21 and 334,4 ±1.31. In this study there was no significant reduction in the absolute expression (log copynumber) gene IL-1β and TNF-α of nasal mucosa after being given medical treatment with NaCl 0,9% nasal wash.

Quantitative Proteomic Analysis of Human Seminal Plasma from Normozoospermic and Asthenozoospermic Individuals

Seminal plasma is a complex mixture of secretions from various glands in the male genital tract. Compared to sperm cells, it contains important proteins that are both directly and indirectly associated with sperm motility. Here, we constructed quantitative proteomes of human seminal plasma from three normozoospermic and asthenozoospermic individuals. A total of 524 proteins were identified, and 366 of them were found to be quantified in all six samples. We first investigated the absolute expression features of these proteins and found that the variations of protein identification among different samples and other published datasets were mainly due to some lowly expressed proteins. By integration of various proteomic datasets and bioinformatics databases, we comprehensively annotated the biological functions, physiological originations, and disease associations of these proteins. We found that our dataset could benefit the studies of both male infertility and other male diseases. Finally, based on the relative expression values determined by chemical labeling, we identified a total of 29 differentially expressed proteins, which could be used as candidate targets for studying the molecular bases of sperm motility or developing precise diagnostic biomarkers of asthenozoospermia. We further successfully verified the expression trends of four representative proteins by Western blotting. Compared to a previous dataset based on label-free quantification, our results showed that most of the important proteins could be identified in the sample collected only once for each individual, providing the bases for personalized examination of seminal plasma proteins in clinic.