In development, timing is of the utmost importance, and the timing of various developmental processes are often changed during evolution. During human evolution sexual maturation has been delayed relative to other primates and this may have played a critical role for both the increase of human brain size and the rise of human-specific cognitive traits .
Transcriptional neoteny in the human brain.
Sex, Age, Specimen part
View SamplesIn development, timing is of the utmost importance, and the timing of various developmental processes are often changed during evolution. During human evolution sexual maturation has been delayed relative to other primates and this may have played a critical role for both the increase of human brain size and the rise of human-specific cognitive traits .
Transcriptional neoteny in the human brain.
Sex, Age, Specimen part
View SamplesIn development, timing is of the utmost importance, and the timing of various developmental processes are often changed during evolution.
Transcriptional neoteny in the human brain.
Sex, Age, Specimen part
View SamplesPurpose: Foxp2 is the first and for now the only gene connected to speech and language in humans. Two aminoacid substitutions took place in this protein during recent human evolution, after our split from the last common ancestor with chimpanzees, and are most likely to have undergone positive selection in human lineage (Enard et al., 2002). Methods: Transgenic mice in which the wild-type (murine) version of Foxp2 was replaced with the one bearing two human-specific amino acid substitutions (i.e. "humanized" Foxp2) - Foxp2hum/hum, have been compared to their wild-type (WT) counterparts in terms of behavior, electrophysiology and striatal gene expression. The latter was analyzed through RNA-sequencing performed on pooled indexed libraries on three flow cells on Illumina GAIIx. The reads were mapped to mouse genome (mm9) by TopHat 1.4.1 and were counted using Bedtools. mRNA profiles were obtained with more than 20 million reads for every sample. Differential gene expression was analyzed with DESeq using multifactor model (Anders and Huber, 2010). Results: Wild-type and Foxp2hum/hum mice did not show any significant differences in expression at individual gene level, neither in dorsomedial nor in dorsolateral striatum. However, when genes were grouped into functional categories and analyzed accordingly, this revealed a significant downregulation of functional categories related to synaptic signalling and plasticity in dorsomedial striatum of Foxp2hum/hum mice. Overall design: RNA-sequencing was performed on dorsomedial and dorsolateral striatum of wild-type and Foxp2hum/hum mice, on three flow cells Illumina GAIIx. The libraries from each sample were indexed and pooled together.
Humanized Foxp2 accelerates learning by enhancing transitions from declarative to procedural performance.
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View SamplesRNA from circulating blood reticulocytes was utilized to provide a robust description of genes transcribed at the final stages of erythroblast maturation. After depletion of leukocytes and platelets, Affymetrix HG-U133 arrays were hybridized with probe from total RNA isolated from blood sampled from 14 umbilical cords and 14 healthy adult humans.
The human reticulocyte transcriptome.
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View SamplesCarbon monoxide (CO) is an endogenous messenger that suppresses inflammation, modulates apoptosis and promotes vascular remodeling. Here, microarrays were employed to globally characterize the CO (250 ppm) suppression of early (1 h) LPS-induced inflammation in human monocytic THP-1 cells. CO suppressed 79 of 101 immediate-early genes induced by LPS; 19% (15/79) were transcription factors and most others were cytokines, chemokines and immune response genes. The prototypic effects of CO on transcription and protein production occurred early but decreased rapidly. CO activated p38 MAPK, ERK1/2 and Akt and caused an early and transitory delay in LPS-induced JNK activation. However, selective inhibitors of these kinases failed to block CO suppression of LPS-induced IL-1beta, an inflammation marker. Of CO-suppressed genes, 81% (64/79) were found to have promoters with putative NF-kappaB binding sites. CO was subsequently shown to block LPS-induced phosphorylation and degradation of IkappaBalpha in human monocytes, thereby inhibiting NF-kappaB signal transduction. CO broadly suppresses the initial inflammatory response of human monocytes to LPS by reshaping proximal events in TLR4 signal transduction such as stress kinase responses and early NF-kappaB activation. These rapid, but transient effects of CO may have therapeutic applications in acute pulmonary and vascular injury.
Carbon monoxide blocks lipopolysaccharide-induced gene expression by interfering with proximal TLR4 to NF-kappaB signal transduction in human monocytes.
Specimen part, Treatment
View SamplesPreviously we reported that a recombinant vaccinia virus (VACV) carrying a light-emitting fusion gene enters, replicates in, and reveals the locations of tumors in mice. A new recombinant VACV, GLV-1h68, as a simultaneous diagnostic and therapeutic agent, was constructed by inserting three expression cassettes (encoding Renilla luciferase-green fluorescent protein (RUC-GFP) fusion, b-galactosidase, and b-glucuronidase) into the F14.5L, J2R (encoding thymidine kinase, TK), and A56R (encoding hemagglutinin, HA) loci of the viral genome, respectively. Intravenous (i.v.) injections of GLV-1h68 (1 107 pfu/mouse) into nude mice with established (500 mm3) subcutaneous (s.c.) GI-101A human breast tumors were used to evaluate its toxicity, tumor targeting specificity and oncolytic efficacy. GLV-1h68 demonstrated an enhanced tumor targeting specificity and much reduced toxicity compared to its parental LIVP strains. The tumors colonized by GLV-1h68 exhibited growth, inhibition, and regression phases followed by tumor eradication within 130 days in 95% of the mice tested. Tumor regression in live animals was monitored in real time based on decreasing light emission, hence demonstrating the concept of a combined oncolytic virus-mediated tumor diagnosis and therapy system. Transcriptional profiling of regressing tumors based on a mouse-specific platform revealed gene expression signatures consistent with immune defense activation, inclusive of interferon stimulated genes (STAT-1 and IRF-7), cytokines, chemokines and innate immune effector function. These findings suggest that immune activation may combine with viral oncolysis to induce tumor eradication in this model, providing a novel perspective for the design of oncolytic viral therapies for human cancers.
Eradication of solid human breast tumors in nude mice with an intravenously injected light-emitting oncolytic vaccinia virus.
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View SamplesBacterial superantigens are virulence factors that cause toxic shock syndrome. Here, the genome-wide, temporal response of mice to lethal intranasal staphylococcal enterotoxin B (SEB) was investigated in six tissues (PBMC, lung, spleen, kidney, heart, Liver).The earliest responses and largest number of affected genes occurred in tissues (PBMCs, spleen and lung) with the highest content of both T-cells and monocyte/macrophages, the direct cellular targets of SEB. In contrast, the response of liver, kidney and heart was delayed and involved fewer genes, but revealed a dominant genetic program that was seen in all 6 tissues. Many of the 85 uniquely annotated transcripts participating in this shared genomic response have not been previously linked to SEB. Global gene-expression changes measured serially across multiple organs identified new candidate mechanisms of SEB-induced death.
Late multiple organ surge in interferon-regulated target genes characterizes staphylococcal enterotoxin B lethality.
Sex, Specimen part
View SamplesIn addition to being causally linked to the formation of multiple tumor types, tobacco use has been associated with decreased anticancer treatment efficacy and reduced survival time. A detailed understanding of the cellular mechanisms that are affected by tobacco smoke should facilitate the development of improved preventive and therapeutic strategies. We have investigated the effects of a tobacco smoke (TS) extract on the transcriptome of MSK-Leuk1 cells, a cellular model of oral leukoplakia. Using Affymetrix HGU133 Plus 2 arrays, 411 differentially expressed probesets were identified. The observed transcriptome changes were grouped according to functional information, and translated into molecular interaction network maps and signaling pathways. Pathways related to cellular proliferation, inflammation, apoptosis and tissue injury appeared to be perturbed. Analysis of networks connecting the affected genes identified specific molecular interactions, hubs and key transcription regulators affected by TS. Thus TS was found to induce several EGFR ligands forming an EGFR-centered molecular interaction network, as well as several AhR-dependent genes, including the xenobiotic metabolizing enzymes CYP1A1 and CYP1B1. Notably, the latter findings in vitro are consistent with our parallel finding that levels of CYP1A1 and CYP1B1 were increased in oral mucosa of smokers. Collectively, these results offer insights into the mechanisms underlying the procarcinogenic effects of TS and raise the possibility that inhibitors of EGFR or AhR signaling will prevent or delay the development of tobacco smoke-related tumors. Moreover, the inductive effects of TS on xenobiotic metabolizing enzymes may help explain reduced efficacy of chemotherapy, and suggest targets for chemopreventive agents in smokers.
Effects of tobacco smoke on gene expression and cellular pathways in a cellular model of oral leukoplakia.
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View SamplesPneumocystis is a pathogen of immunocompromised hosts but can also infect healthy hosts, in whom infection is rapidly controlled and cleared. To better understand the immune mechanisms contributing to clearance of infection, microarray methods were used to examine differential gene expression in the lungs of C57BL/6 and CD40 ligand knock-out (CD40L-KO) mice over time following exposure to Pneumocystis. Immuncompetent C57BL/6 mice, which control and clear infection efficiently, showed a robust response to infection characterized by the upregulation of 349 primarily immune-response associated genes. Temporal changes in the expression of these genes suggested that there was an early (week 2) primarily innate response, that waned without controlling infection; this were followed by primarily adaptive immune responses that peaked at week 5 and successfully cleared the infection. In conjunction with the latter, there was an increased expression of B cell associated (immunoglobulin) genes at week 6 that persisted through 11 weeks. In contrast, CD40L-KO mice, which are highly susceptible to developing severe Pneumocystis pneumonia, showed essentially no upregulation of immune-response associated genes at days 35 to 75. Immunohistochemical staining supported these observations by demonstrating an increase in CD4+, CD68+, and CD19+ cells in C57BL/6 but not CD40L-KO mice. Thus, the healthy host demonstrates a robust biphasic response to infection by Pneumocystis; CD40 ligand is an essential upstream regulator of the adaptive immune responses that efficiently control infection and prevent development of progressive pneumonia.
Immune responses to Pneumocystis murina are robust in healthy mice but largely absent in CD40 ligand-deficient mice.
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