Modulation Of Transcriptome Research Articles

Modulation of laccase transcriptome during biodegradation of naphthalene by white rot fungus Pleurotus ostreatus.

Biodegradation of polycyclic aromatic hydrocarbons (PAHs) using Pleurotus ostreatus was investigated in the current study along with the expression levels of laccase genes involved in biodegradation under variable conditions. Biodegradation of PAHs (naphthalene, anthracene, and 1,10-phenanthroline) was detected spectrophotometrically. Recorded data revealed that biodegradation of the tested PAHs was time dependent. Elevated level of naphthalene biodegradation (86.47%) was observed compared to anthracene (27.87%) and 1,10-phenanthroline (24.51%) within 3days post incubation. Naphthalene was completely degraded within 5days. Further incubation enhanced the biodegradation of both anthracene and 1,10-phenanthroline until reaches 93.69% and 92.00% biodegradation of the initial concentration within an incubation period of 11 and 14days, respectively. Naphthalene was selected as a PAH model. HPLC and thin layer chromatography of naphthalene biodegradation products at time intervals proposed that naphthalene was first degraded to α- and β-naphthol which was further metabolized to salicylic and benzoic acid. The metabolic pathway of naphthalene degradation by this fungus was elucidated based on the detected metabolites. The expression profile of six laccase isomers was evaluated using real-time PCR. The transcriptome of the fungal laccase isomers recorded higher levels of transcription under optimized fermentation conditions especially in presence of both naphthalene and Tween 80. The accumulation of such useful metabolites from the biodegradation of PAH pollutants recommended white rot fungus as a potential candidate for production of platform chemicals from PAH wastes.

Ethanol-Induced Behavioral Sensitization Alters the Synaptic Transcriptome and Exon Utilization in DBA/2J Mice.

Alcoholism is a complex behavioral disorder characterized by loss of control in limiting intake, and progressive compulsion to seek and consume ethanol. Prior studies have suggested that the characteristic behaviors associated with escalation of drug use are caused, at least in part, by ethanol-evoked changes in gene expression affecting synaptic plasticity. Implicit in this hypothesis is a dependence on new protein synthesis and remodeling at the synapse. It is well established that mRNA can be transported to distal dendritic processes, where it can undergo localized translation. It is unknown whether such modulation of the synaptic transcriptome might contribute to ethanol-induced synaptic plasticity. Using ethanol-induced behavioral sensitization as a model of neuroplasticity, we investigated whether repeated exposure to ethanol altered the synaptic transcriptome, contributing to mechanisms underlying subsequent increases in ethanol-evoked locomotor activity. RNAseq profiling of DBA/2J mice subjected to acute ethanol or ethanol-induced behavioral sensitization was performed on frontal pole synaptoneurosomes to enrich for synaptic mRNA. Genomic profiling showed distinct functional classes of mRNA enriched in the synaptic vs. cytosolic fractions, consistent with their role in synaptic function. Ethanol sensitization regulated more than twice the number of synaptic localized genes compared to acute ethanol exposure. Synaptic biological processes selectively perturbed by ethanol sensitization included protein folding and modification as well as and mitochondrial respiratory function, suggesting repeated ethanol exposure alters synaptic energy production and the processing of newly translated proteins. Additionally, marked differential exon usage followed ethanol sensitization in both synaptic and non-synaptic cellular fractions, with little to no perturbation following acute ethanol exposure. Altered synaptic exon usage following ethanol sensitization strongly affected genes related to RNA processing and stability, translational regulation, and synaptic function. These genes were also enriched for targets of the FMRP RNA-binding protein and contained consensus sequence motifs related to other known RNA binding proteins, suggesting that ethanol sensitization altered selective mRNA trafficking mechanisms. This study provides a foundation for investigating the role of ethanol in modifying the synaptic transcriptome and inducing changes in synaptic plasticity.

Data-driven human transcriptomic modules determined by independent component analysis

BackgroundAnalyzing the human transcriptome is crucial in advancing precision medicine, and the plethora of over half a million human microarray samples in the Gene Expression Omnibus (GEO) has enabled us to better characterize biological processes at the molecular level. However, transcriptomic analysis is challenging because the data is inherently noisy and high-dimensional. Gene set analysis is currently widely used to alleviate the issue of high dimensionality, but the user-defined choice of gene sets can introduce biasness in results.In this paper, we advocate the use of a fixed set of transcriptomic modules for such analysis. We apply independent component analysis to the large collection of microarray data in GEO in order to discover reproducible transcriptomic modules that can be used as features for machine learning. We evaluate the usability of these modules across six studies, and demonstrate (1) their usage as features for sample classification, and also their robustness in dealing with small training sets, (2) their regularization of data when clustering samples and (3) the biological relevancy of differentially expressed features.ResultsWe identified 139 reproducible transcriptomic modules, which we term fundamental components (FCs). In studies with less than 50 samples, FC-space classification model outperformed their gene-space counterparts, with higher sensitivity (p < 0.01). The models also had higher accuracy and negative predictive value (p < 0.01) for small data sets (less than 30 samples). Additionally, we observed a reduction in batch effects when data is clustered in the FC-space. Finally, we found that differentially expressed FCs mapped to GO terms that were also identified via traditional gene-based approaches.ConclusionsThe 139 FCs provide biologically-relevant summarization of transcriptomic data, and their performance in low sample settings suggest that they should be employed in such studies in order to harness the data efficiently.

A novel method of using Deep Belief Networks and genetic perturbation data to search for yeast signaling pathways.

Perturbing a signaling system with a serial of single gene deletions and then observing corresponding expression changes in model organisms, such as yeast, is an important and widely used experimental technique for studying signaling pathways. People have developed different computational methods to analyze the perturbation data from gene deletion experiments for exploring the signaling pathways. The most popular methods/techniques include K-means clustering and hierarchical clustering techniques, or combining the expression data with knowledge, such as protein-protein interactions (PPIs) or gene ontology (GO), to search for new pathways. However, these methods neither consider nor fully utilize the intrinsic relation between the perturbation of a pathway and expression changes of genes regulated by the pathway, which served as the main motivation for developing a new computational method in this study. In our new model, we first find gene transcriptomic modules such that genes in each module are highly likely to be regulated by a common signal. We then use the expression status of those modules as readouts of pathway perturbations to search for up-stream pathways. Systematic evaluation, such as through gene ontology enrichment analysis, has provided evidence that genes in each transcriptomic module are highly likely to be regulated by a common signal. The PPI density analysis and literature search revealed that our new perturbation modules are functionally coherent. For example, the literature search revealed that 9 genes in one of our perturbation module are related to cell cycle and all 10 genes in another perturbation module are related by DNA damage, with much evidence from the literature coming from in vitro or/and in vivo verifications. Hence, utilizing the intrinsic relation between the perturbation of a pathway and the expression changes of genes regulated by the pathway is a useful method of searching for signaling pathways using genetic perturbation data. This model would also be suitable for analyzing drug experiment data, such as the CMap data, for finding drugs that perturb the same pathways.

Analysis of the Long-Lived Responses Induced by Immunostimulants and Their Effects on a Viral Infection in Zebrafish (Danio rerio).

In recent years, the innate immune response has gained importance since evidence indicates that after an adequate priming protocol, it is possible to obtain some prolonged and enhanced immune responses. Nevertheless, several factors, such as the timing and method of administration of the immunostimulants, must be carefully considered. An inappropriate protocol can transform the treatments into a double-edged sword for the teleost immune system, resulting in a stressful and immunosuppressive state. In this work, we analyzed the long-term effects of different stimuli (β-glucans, lipopolysaccharide, and polyinosinic:polycytidylic acid) on the transcriptome modulation induced by Spring Viremia Carp Virus (SVCV) in adult zebrafish (Danio rerio) and on the mortality caused by this infection. At 35 days post-immunostimulation, the transcriptome was found to be highly altered compared to that of the control fish, and these stimuli also conditioned the response to SVCV challenge, especially in the case of β-glucans. No protection against SVCV was found with any of the stimuli, and non-significant higher mortalities were even observed, especially with β-glucans. However, in the short term (pre-stimulation with β-glucan and infection after 7 days), slight protection was observed after infection. The transcriptome response in the zebrafish kidney at 35 days posttreatment with β-glucans revealed a significant response associated with stress and immunosuppression. The identification of genes that were differentially expressed before and after the infection seemed to indicate a high energy cost of the immunostimulation that was prolonged over time and could explain the lack of protection against SVCV. Differential responses to stress and alterations in lipid metabolism, the tryptophan–kynurenine pathway, and interferon-gamma signaling seem to be some of the mechanisms involved in this response, which represents the end of trained immunity and the beginning of a stressful state characterized by immunosuppression.

LTR-retrotransposon transcriptome modulation in response to endotoxin-induced stress in PBMCs

BackgroundHuman Endogenous Retroviruses (HERVs) and Mammalian apparent LTR-retrotransposons (MaLRs) represent the 8% of our genome and are distributed among our 46 chromosomes. These LTR-retrotransposons are thought to be essentially silent except in cancer, autoimmunity and placental development. Their Long Terminal Repeats (LTRs) constitute putative promoter or polyA regulatory sequences. In this study, we used a recently described high-density microarray which can be used to study HERV/MaLR transcriptome including 353,994 HERV/MaLR loci and 1559 immunity-related genes.ResultsWe described, for the first time, the HERV transcriptome in peripheral blood mononuclear cells (PBMCs) using a cellular model mimicking inflammatory response and monocyte anergy observed after septic shock. About 5.6% of the HERV/MaLR repertoire is transcribed in PBMCs. Roughly one-tenth [5.7–13.1%] of LTRs exhibit a putative constitutive promoter or polyA function while one-quarter [19.5–27.6%] may shift from silent to active. Evidence was given that some HERVs/MaLRs and genes may share similar regulation control under lipopolysaccharide (LPS) stimulation conditions. Stimulus-dependent response confirms that HERV expression is tightly regulated in PBMCs. Altogether, these observations make it possible to integrate 62 HERVs/MaLRs and 26 genes in 11 canonical pathways and suggest a link between HERV expression and immune response. The transcriptional modulation of HERVs located close to genes such as OAS2/3 and IFI44/IFI44L or at a great distance from genes was discussed.ConclusionThis microarray-based approach revealed the expression of about 47,466 distinct HERV loci and identified 951 putative promoter LTRs and 744 putative polyA LTRs in PBMCs. HERV/MaLR expression was shown to be tightly modulated under several stimuli including high-dose and low-dose LPS and Interferon-γ (IFN-γ). HERV incorporation at the crossroads of immune response pathways paves the way for further functional studies and analyses of the HERV transcriptome in altered immune responses in vivo such as in sepsis.

Perioperative inhibition of β-adrenergic and COX2 signaling in a clinical trial in breast cancer patients improves tumor Ki-67 expression, serum cytokine levels, and PBMCs transcriptome

Catecholamines and prostaglandins are secreted abundantly during the perioperative period in response to stress and surgery, and were shown by translational studies to promote tumor metastasis. Here, in a phase-II biomarker clinical trial in breast cancer patients (n = 38), we tested the combined perioperative use of the β-blocker, propranolol, and the COX2-inhibitor, etodolac, scheduled for 11 consecutive perioperative days, starting 5 days before surgery. Blood samples were taken before treatment (T1), on the mornings before and after surgery (T2&T3), and after treatment cessation (T4). Drugs were well tolerated. Results based on a-priori hypotheses indicated that already before surgery (T2), serum levels of pro-inflammatory IL-6, CRP, and IFNγ, and anti-inflammatory, cortisol and IL-10, increased. At T2 and/or T3, drug treatment reduced serum levels of the above pro-inflammatory cytokines and of TRAIL, as well as activity of multiple inflammation-related transcription factors (including NFκB, STAT3, ISRE), but not serum levels of cortisol, IL-10, IL-18, IL-8, VEGF and TNFα. In the excised tumor, treatment reduced the expression of the proliferation marker Ki-67, and positively affected its transcription factors SP1 and AhR. Exploratory analyses of transcriptome modulation in PBMCs revealed treatment-induced improvement at T2/T3 in several transcription factors that in primary tumors indicate poor prognosis (CUX1, THRa, EVI1, RORa, PBX1, and T3R), angiogenesis (YY1), EMT (GATA1 and deltaEF1/ZEB1), proliferation (GATA2), and glucocorticoids response (GRE), while increasing the activity of the oncogenes c-MYB and N-MYC. Overall, the drug treatment may benefit breast cancer patients through reducing systemic inflammation and pro-metastatic/pro-growth biomarkers in the excised tumor and PBMCs.

Modulation of the peripheral blood transcriptome by the ingestion of probiotic yoghurt and acidified milk in healthy, young men.

The metabolic health benefits of fermented milks have already been investigated using clinical biomarkers but the development of transcriptomic analytics in blood offers an alternative approach that may help to sensitively characterise such effects. We aimed to assess the effects of probiotic yoghurt intake, compared to non-fermented, acidified milk intake, on clinical biomarkers and gene expression in peripheral blood. To this end, a randomised, crossover study was conducted in fourteen healthy, young men to test the two dairy products. For a subset of seven subjects, RNA sequencing was used to measure gene expression in blood collected during postprandial tests and after two weeks daily intake. We found that the postprandial response in insulin was different for probiotic yoghurt as compared to that of acidified milk. Moreover changes in several clinical biomarkers were associated with changes in the expression of genes representing six metabolic genesets. Assessment of the postprandial effects of each dairy product on gene expression by geneset enrichment analysis revealed significant, similar modulation of inflammatory and glycolytic genes after both probiotic yoghurt and acidified milk intake, although distinct kinetic characteristics of the modulation differentiated the dairy products. The aryl hydrocarbon receptor was a major contributor to the down-regulation of the inflammatory genesets and was also positively associated with changes in circulating insulin at 2h after yoghurt intake (p = 0.05). Daily intake of the dairy products showed little effect on the fasting blood transcriptome. Probiotic yoghurt and acidified milk appear to affect similar gene pathways during the postprandial phase but differences in the timing and the extent of this modulation may lead to different physiological consequences. The functional relevance of these differences in gene expression is supported by their associations with circulating biomarkers.

Differential transcriptome modulation leads to variation in arsenic stress response in Arabidopsis thaliana accessions

Arsenic (As) is a ubiquitous metalloid and a health hazard to millions of people worldwide. The presence of As in groundwater poses a threat as it not only affects crop productivity but also contaminates food chain. Therefore, it is essential to understand molecular mechanisms underlying uptake, transport and accumulation of As in plants. In recent past, natural variation in Arabidopsis thaliana has been utilized to understand molecular and genetic adaptation under different stresses. In this study, responses of Arabidopsis accessions were analyzed at biochemical and molecular levels towards arsenate [As(V)] stress. On the basis of reduction in root length, accessions were categorized into tolerant and sensitive ones towards As(V). Root length analysis led to the identification of Col-0 (<10% reduction) and Slavi-1 (>60% reduction) as the most tolerant and sensitive accessions, respectively. Comparative genome-wide expression analysis revealed differential expression of 168 and 548 genes in Col-0 and Slavi-1, respectively, with 120 common differentially expressed genes. A number of genes associated with defense and stress-response, transport system, regulatory mechanisms and biochemical processes showed differential expression in contrasting accessions. The study provides an insight into the molecular mechanisms associated with stress response and processes involved in adaptation strategies towards As stress.

Langerhans Cells—Programmed by the Epidermis

Langerhans cells (LCs) reside in the epidermis as a dense network of immune system sentinels. These cells determine the appropriate adaptive immune response (inflammation or tolerance) by interpreting the microenvironmental context in which they encounter foreign substances. In a normal physiological, “non-dangerous” situation, LCs coordinate a continuous state of immune tolerance, preventing unnecessary and harmful immune activation. Conversely, when they sense a danger signal, for example during infection or when the physical integrity of skin has been compromised as a result of a trauma, they instruct T lymphocytes of the adaptive immune system to mount efficient effector responses. Recent advances investigating the molecular mechanisms underpinning the cross talk between LCs and the epidermal microenvironment reveal its importance for programming LC biology. This review summarizes the novel findings describing LC origin and function through the analysis of the transcriptomic programs and gene regulatory networks (GRNs). Review and meta-analysis of publicly available datasets clearly delineates LCs as distinct from both conventional dendritic cells (DCs) and macrophages, suggesting a primary role for the epidermal microenvironment in programming LC biology. This concept is further supported by the analysis of the effect of epidermal pro-inflammatory signals, regulating key GRNs in human and murine LCs. Applying whole transcriptome analyses and in silico analysis has advanced our understanding of how LCs receive, integrate, and process signals from the steady-state and diseased epidermis. Interestingly, in homeostasis and under immunological stress, the molecular network in LCs remains relatively stable, reflecting a key evolutionary need related to tissue localization. Importantly, to fulfill their key role in orchestrating antiviral adaptive immune responses, LC share specific transcriptomic modules with other DC types able to cross-present antigens to cytotoxic CD8+ T cells, pointing to a possible evolutionary convergence mechanism. With the development of more advanced technologies allowing delineation of the molecular networks at the level of chromatin organization, histone modifications, protein translation, and phosphorylation, future “omics” investigations will bring in-depth understanding of the complex molecular mechanisms underpinning human LC biology.

A transcribed enhancer dictates mesendoderm specification in pluripotency

Enhancers and long noncoding RNAs (lncRNAs) are key determinants of lineage specification during development. Here, we evaluate remodeling of the enhancer landscape and modulation of the lncRNA transcriptome during mesendoderm specification. We sort mesendodermal progenitors from differentiating embryonic stem cells (ESCs) according to Eomes expression, and find that enhancer usage is coordinated with mesendoderm-specific expression of key lineage-determining transcription factors. Many of these enhancers are associated with the expression of lncRNAs. Examination of ESC-specific enhancers interacting in three-dimensional space with mesendoderm-specifying transcription factor loci identifies MesEndoderm Transcriptional Enhancer Organizing Region (Meteor). Genetic and epigenetic manipulation of the Meteor enhancer reveal its indispensable role during mesendoderm specification and subsequent cardiogenic differentiation via transcription-independent and -dependent mechanisms. Interestingly, Meteor-deleted ESCs are epigenetically redirected towards neuroectodermal lineages. Loci, topologically associating a transcribed enhancer and its cognate protein coding gene, appear to represent therefore a class of genomic elements controlling developmental competence in pluripotency.

Identification of the principal transcriptional regulators for low-fat and high-fat meal responsive genes in small intestine

BackgroundHigh-fat (HF) diet is a well-known cause of obesity. To identify principle transcriptional regulators that could be therapeutic targets of obesity, we investigated transcriptomic modulation in the duodenal mucosa following low-fat (LF) and HF meal ingestion.MethodsWhereas one group of mice was sacrificed after fasting, the others were fed ad libitum with LF or HF meal, and sacrificed 30 min, 1 h and 3 h after the beginning of the meal. A transcriptome analysis of the duodenal mucosa of the 7 groups was conducted using both microarray and serial analysis of gene expression (SAGE) method followed by an Ingenuity Pathways Analysis (IPA).ResultsSAGE and microarray showed that the modulation of a total of 896 transcripts in the duodenal mucosa after LF and/or HF meal, compared to the fasting condition. The IPA identified lipid metabolism, molecular transport, and small molecule biochemistry as top three molecular and cellular functions for the HF-responsive, HF-specific, HF-delay, and LF-HF different genes. Moreover, the top transcriptional regulator for the HF-responsive and HF-specific genes was peroxisome proliferator-activated receptor alpha (PPARα). On the other hand, the LF-responsive and LF-specific genes were related to carbohydrate metabolism, cellular function and maintenance, and cell death/cellular growth and proliferation, and the top transcriptional regulators were forkhead box protein O1 (FOXO1) and cAMP response element binding protein 1 (CREB1), respectively.ConclusionsThese results will help to understand the molecular mechanisms of intestinal response after LF and HF ingestions, and contribute to identify therapeutic targets for obesity and obesity-related diseases.

Transcriptome modulation of bovine trophoblast cells in vitro by Neospora caninum

Neospora caninum is one of the most efficient transplacentally transmitted pathogens in cattle and is a cause of abortion in this domestic species. The invasion and proliferation of Neospora caninum in the placenta and its dissemination to the foetus are crucial events in the outcome of an infection. In the bovine placenta, the placentomes are formed by maternal caruncles, which are delimited by a maternal epithelium and foetal cotyledons, which are delimited by an epithelial layer named the trophoblast. These epithelia form a physical barrier against foetal infection. Furthermore, trophoblast cells act as an innate immune defence at the foetal-maternal interface. Neospora caninum invades and proliferates in trophoblast cells in vitro, but it is unknown whether host cell modulation events, which affect the immune response and other processes in the trophoblast, occur. In this work, we investigated the transcriptomic modulation by Neospora caninum infection in the bovine trophoblast cell line F3. In addition, two Neospora caninum isolates with marked differences in virulence, Nc-Spain1H and the Nc-Spain7, were used in this study to investigate the influence of these isolates in F3 modulation. The results showed a clear influence on extracellular matrix reorganisation, cholesterol biosynthesis and the transcription factor AP-1 network. Interestingly, although differences in the transcriptome profiles induced by each isolate were observed, specific isolate-modulated processes were not identified, suggesting very similar regulation in both isolates. Differential expression of the N. caninum genes between both isolates was also investigated. Genes involved in host cell attachment and invasion (SAG-related and microneme proteins), glideosome, rhoptries, metabolic processes, cell cycle and stress response were differentially expressed between the isolates, which could explain their variability. This study provides a global view of Neospora caninum interactions with bovine trophoblast cells and of the intra-specific differences between two Neospora caninum isolates with biological differences.

A signal-based method for finding driver modules of breast cancer metastasis to the lung

Tumor metastasis is mainly caused by somatic genomic alterations (SGAs) that perturb pathways regulating metastasis-relevant activities and thus help the primary tumor to adapt to the new microenvironment. Identifying drivers of metastasis, i.e. SGAs, sheds light on the metastasis mechanism and provides guidance for targeted therapy. In this paper, we introduce a novel method to search for SGAs driving breast cancer metastasis to the lung. First, we search for transcriptomic modules with genes that are differentially expressed in breast cell lines with strong metastatic activities to the lung and co-expressed in a large number of breast tumors. Then, for each transcriptomic module, we search for a set of SGA genes (driver modules) such that genes in each driver module carry a common signal regulating the transcriptomic module. Evaluations indicate that many genes in driver modules are indeed related to metastasis, and our methods have identified many new driver candidates. We further choose two novel metastatic driver genes, BCL2L11 and CDH9, for in vitro verification. The wound healing assay reveals that inhibiting either BCL2L11 or CDH9 will enhance the migration of cell lines, which provides evidence that these two genes are suppressors of tumor metastasis.

Sexual dimorphism of the pulmonary transcriptome in neonatal hyperoxic lung injury: identification of angiogenesis as a key pathway.

Bronchopulmonary dysplasia (BPD) is characterized by impaired alveolar secondary septation and vascular growth. Exposure to high concentrations of oxygen (hyperoxia) contributes to the development of BPD. The male sex is considered an independent risk factor for the development of BPD. The reasons underlying sexually dimorphic outcomes in premature neonates are not known. We hypothesized that sex-specific modulation of biological processes in the lung under hyperoxic conditions contributes to sex-based differences. Neonatal male and female mice (C57BL/6) were exposed to hyperoxia [95% [Formula: see text], postnatal day (PND) 1-5: saccular stage of lung development] and euthanized on PND 7 or 21. Pulmonary gene expression was studied using RNA-Seq on the Illumina HiSeq 2500 platform. Analysis of the pulmonary transcriptome revealed differential sex-specific modulation of crucial pathways such as angiogenesis, response to hypoxia, inflammatory response, and p53 pathway. Candidate genes from these pathways were validated at the mRNA level by qPCR. Analysis also revealed sex-specific differences in the modulation of crucial transcription factors. Focusing on the differential modulation of the angiogenesis pathway, we also showed sex-specific differential activation of Hif-1α-regulated genes using ChIP-qPCR and differences in expression of crucial genes (Vegf, VegfR2, and Phd2) modulating angiogenesis. We demonstrate the translational relevance of our findings by showing that our murine sex-specific differences in gene expression correlate with those from a preexisting human BPD data set. In conclusion, we provide novel molecular insights into differential sex-specific modulation of the pulmonary transcriptome in neonatal hyperoxic lung injury and highlight angiogenesis as one of the crucial differentially modulated pathways.

Transcriptome modulation by hydrocortisone in severe burn shock: ancillary analysis of a prospective randomized trial

BackgroundDespite shortening vasopressor use in shock, hydrocortisone administration remains controversial, with potential harm to the immune system. Few studies have assessed the impact of hydrocortisone on the transcriptional response in shock, and we are lacking data on burn shock. Our objective was to assess the hydrocortisone-induced transcriptional modulation in severe burn shock, particularly modulation of the immune response.MethodsWe collected whole blood samples during a randomized controlled trial assessing the efficacy of hydrocortisone administration in burn shock. Using whole genome microarrays, we first compared burn patients (n = 32) from the placebo group to healthy volunteers to describe the transcriptional modulation induced by burn shock over the first week. Then we compared burn patients randomized for either hydrocortisone administration or placebo, to assess hydrocortisone-induced modulation.ResultsStudy groups were similar in terms of severity and major outcomes, but shock duration was significantly reduced in the hydrocortisone group. Many genes (n = 1687) were differentially expressed between burn patients and healthy volunteers, with 85% of them exhibiting a profound and persistent modulation over seven days. Interestingly, we showed that hydrocortisone enhanced the shock-associated repression of adaptive, but also innate immunity.ConclusionsWe found that the initial host response to burn shock encompasses wide and persistent modulation of gene expression, with profound modulation of pathways associated with metabolism and immunity. Importantly, hydrocortisone administration may worsen the immunosuppression associated with severe injury. These data should be taken into account in the risk ratio of hydrocortisone administration in patients with inflammatory shock.Trial registrationClinicalTrials.gov, NCT00149123. Registered on 6 September 2005.

Nitric oxide mediated transcriptional modulation enhances plant adaptive responses to arsenic stress

Arsenic (As) contamination in rice leads to yield decline and causes carcinogenic risk to human health. Although the role of nitric oxide (NO) in reducing As toxicity is known, NO-mediated genetic modulation in the plant during arsenic toxicity has not yet been established. We analyzed the key components of NO metabolism and the correlations between NO interaction and arsenic stress using rice as a relevant model plant. Illumina sequencing was used to investigate the NO-mediated genome-wide temporal transcriptomic modulation in rice root upon AsIII exposure during 12 days (d) of the growth period. Sodium nitroprusside (SNP) was used as NO donor. SNP supplementation resulted in marked decrease in ROS, cell death and As accumulation during AsIII stress. NO was found to modulate metal transporters particularly NIP, NRAMP, ABC and iron transporters, stress related genes such as CytP450, GSTs, GRXs, TFs, amino acid, hormone(s), signaling and secondary metabolism genes involved in As detoxification. We detected NO-mediated change in jasmonic acid (JA) content during AsIII stress. The study infers that NO reduces AsIII toxicity through modulating regulatory networks involved in As detoxification and JA biosynthesis.

Progressive modulation of the human olfactory bulb transcriptome during Alzheimer´s disease evolution: novel insights into the olfactory signaling across proteinopathies.

Alzheimer´s disease (AD) is characterized by progressive dementia, initially presenting olfactory dysfunction. Despite the olfactory bulb (OB) is the first central structure of the olfactory pathway, we lack a complete molecular characterization of the transcriptional events that occurs in this olfactory area during AD progression. To address this gap in knowledge, we have assessed the genome-wide expression in postmortem OBs from subjects with varying degree of AD pathology. A stage-dependent deregulation of specific pathways was observed, revealing transmembrane transport, and neuroinflammation as part of the functional modules that are disrupted across AD grading. Potential drivers of neurodegeneration predicted by network-driven transcriptomics were monitored across different types of dementia, including progressive supranuclear palsy (PSP), mixed dementia, and frontotemporal lobar degeneration (FTLD). Epidermal growth factor receptor (EGFR) expression was significantly increased in the OB of AD and mixed dementia subjects. Moreover, a significant increment in the activation of signal transducer and activator of transcription 3 (STAT3) was exclusively detected in advanced AD stages, whereas total STAT3 levels were specifically overexpressed in mixed dementia. Furthermore, transcription factors deregulated in the OB of mixed dementia subjects such as cAMP Responsive Element Binding Protein 1 (CREB1) and AP-1 Transcription Factor Subunit (c-Jun) were not differentially modulated at olfactory level across AD grading. On the other hand, olfactory expression of this signal transducer panel was unchanged in PSP and FTLD subjects. Taken together, this study unveils cross-disease similarities and differences for specific signal transducers, providing mechanistic clues to the intriguing divergence of AD pathology across proteinopathies.

Intestinal transcriptome modulation by functional diets in rainbow trout: A high-throughput sequencing appraisal to highlight GALT immunomodulation

Functional ingredients such as pre- and probiotics are used in aquaculture to improve fish condition, modulating microbiota and promoting a healthy intestinal functioning. They also exert an active effect on the gut associated lymphoid tissue (GALT), stimulating the immune system. However, the molecular underpinnings of pre- and probiotics effect on intestinal mucosa are still unknown. This study investigated the intestinal mucosa transcriptome modulation when fish were fed functional diets and kept at different stocking densities. Juvenile rainbow trout were kept at low (LD-3Kgm-3) and high density (HD-40 kgm-3) and fed for 30 days functional diets with the prebiotic mannanoligosaccharide (PRE-0.6%), the probiotic Saccharomyces cerevisiae (PRO-0.5%), the mixture of both (MIX) and a control diet (CTRL). Intestinal transcriptome was evaluated by high-throughput sequencing and blood plasma for biochemical parameters. Fish fed functional diets presented better condition regardless density, and that functional diets modulate intestinal transcriptome in different manner depending on the stocking density. At LD, fish from PRO presented stronger modulation with the majority of transcripts being down-regulated, including the immune related ones, whereas at HD both PRO and MIX groups were more modulated, when comparing to the respective CTRL groups. Density had an overwhelming suppressive effect on the immune-related genes, but this effect was counteracted by feeding functional diets, especially in fish fed with probiotics. This study shows for the first time the intestinal transcriptomic modulation when fish are fed functional diets at different stocking densities, and it shows the mitigating effect of these diets against deleterious conditions such as high density.

Sumoylation as an Integral Mechanism in Bacterial Infection and Disease Progression.

Post translational modification pathways regulate fundamental processes of cells and thus govern vital functions. Among these, particularly the modification with Small Ubiquitin-like Modifiers (SUMO) is being recognized as a pathway crucial for cell homeostasis and health. Understandably, bacterial pathogens intervene with the SUMO pathway of the host for ensuring successful infection. Among the bacterial pathogens known to target host sumoylation varied points of intervention are utilized. Majority of them including Salmonella Typhimurium, Shigella flexneri and Listeria monocytogenes target the E2 conjugating enzyme Ubc9. While others, such as Xanthomonase compestris, target the desumoylation machineries mimicking cysteine protease activity. Still others such as Ehrlichia chaffeensis and Anaplasma phagocytophilum utilize host SUMO-machinery for sumoylating their own effectors. Together such changes lead to modulation of host proteome and transcriptome thereby leading to major alterations in signal transduction that favor invasion and bacterial multiplication. Such interplay between bacterial pathogens and host sumoylation has added a new dimension to host-pathogen biology and its understanding could be vital for developing potential therapeutic intervention strategies.