Conceptualizing New Product Buzz

What is buzz? Just a trendy word for WOM? A theories-in-use approach is employed to develop a rich understanding of the conceptual nature of buzz. Consumers perceive buzz to comprise the amount and pervasiveness of search, communication, and participatory activities. Secondary data finds this multi-dimensional operationalization to improve empirical analyses

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

X-ray structure of glutathione S-transferase from Schistosoma japonicum in a new crystal form reveals flexibility of the substrate-binding site

The crystal structure of the 26 kDa glutathione S-transferase from S. japonicum (SjGST) was determined at 3 Å resolution in the new space group P212121. The structure of orthorhombic SjGST reveals unique features of the ligand-binding site and dimer interface when compared with previously reported structures

Ibuprofen disrupts steroidogenesis in the human fetal testis.

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Interaction of the NRF2 and p63 transcription factors promotes keratinocyte proliferation in the epidermis

Epigenetic regulation of cell and tissue function requires the coordinated action of transcription factors. However, their combinatorial activities during regeneration remain largely unexplored. Here, we discover an unexpected interaction between the cytoprotective transcription factor NRF2 and p63- a key player in epithelial morphogenesis. Chromatin immunoprecipitation combined with sequencing and reporter assays identifies enhancers and promoters that are simultaneously activated by NRF2 and p63 in human keratinocytes. Modeling of p63 and NRF2 binding to nucleosomal DNA suggests their chromatin-assisted interaction. Pharmacological and genetic activation of NRF2 increases NRF2-p63 binding to enhancers and promotes keratinocyte proliferation, which involves the common NRF2-p63 target cyclin-dependent kinase 12. These results unravel a collaborative function of NRF2 and p63 in the control of epidermal renewal and suggest their combined activation as a strategy to promote repair of human skin and other stratified epithelia.ISSN:1362-4962ISSN:0301-561

Interaction of the NRF2 and p63 transcription factors promotes keratinocyte proliferation in the epidermis

Epigenetic regulation of cell and tissue function requires the coordinated action of transcription factors. However, their combinatorial activities during regeneration remain largely unexplored. Here, we discover an unexpected interaction between the cytoprotective transcription factor NRF2 and p63- a key player in epithelial morphogenesis. Chromatin immunoprecipitation combined with sequencing and reporter assays identifies enhancers and promoters that are simultaneously activated by NRF2 and p63 in human keratinocytes. Modeling of p63 and NRF2 binding to nucleosomal DNA suggests their chromatin-assisted interaction. Pharmacological and genetic activation of NRF2 increases NRF2-p63 binding to enhancers and promotes keratinocyte proliferation, which involves the common NRF2-p63 target cyclin-dependent kinase 12. These results unravel a collaborative function of NRF2 and p63 in the control of epidermal renewal and suggest their combined activation as a strategy to promote repair of human skin and other stratified epithelia.ISSN:1362-4962ISSN:0301-561

Differentially Expressed MicroRNAs in Meningiomas Grades I and II Suggest Shared Biomarkers with Malignant Tumors

Meningiomas represent the most common primary tumors of the central nervous system, but few microRNA (miRNA) profiling studies have been reported so far. Deep sequencing of small RNA libraries generated from two human meningioma biopsies WHO grades I (benign) and II (atypical) were compared to excess dura controls. Nineteen differentially expressed miRNAs were validated by RT-qPCR using tumor RNA from 15 patients and 5 meninges controls. Tumor suppressor miR-218 and miR-34a were upregulated relative to normal controls, however, miR-143, miR-193b, miR-451 and oncogenic miR-21 were all downregulated. From 10 selected putative mRNA targets tested by RT-qPCR only four were differentially expressed relative to normal controls. PTEN and E-cadherin (CDH1) were upregulated, but RUNX1T1 was downregulated. Proliferation biomarker p63 was upregulated with nuclear localization, but not detected in most normal arachnoid tissues. Immunoreactivity of E-cadherin was detected in the outermost layer of normal arachnoids, but was expressed throughout the tumors. Nuclear Cyclin D1 expression was positive in all studied meningiomas, while its expression in arachnoid was limited to a few trabecular cells. Meningiomas of grades I and II appear to share biomarkers with malignant tumors, but with some additional tumor suppressor biomarkers expression. Validation in more patients is of importance

CFTR Expression Analysis for Subtyping of Human Pancreatic Cancer Organoids

Background. Organoid cultures of human pancreatic ductal adenocarcinoma (PDAC) have become a promising tool for tumor subtyping and individualized chemosensitivity testing. PDACs have recently been grouped into different molecular subtypes with clinical impact based on cytokeratin-81 (KRT81) and hepatocyte nuclear factor 1A (HNF1A). However, a suitable antibody for HNF1A is currently unavailable. The present study is aimed at establishing subtyping in PDAC organoids using an alternative marker. Methods. A PDAC organoid biobank was generated from human primary tumor samples containing 22 lines. Immunofluorescence staining was established and done for 10 organoid lines for cystic fibrosis transmembrane conductance regulator (CFTR) and KRT81. Quantitative real-time PCR (qPCR) was performed for CFTR and HNF1A. A chemotherapeutic drug response analysis was done using gemcitabine, 5-FU, oxaliplatin, and irinotecan. Results. A biobank of patient-derived PDAC organoids was established. The efficiency was 71% (22/31) with 68% for surgical resections and 83% for fine needle aspirations. Organoids could be categorized into the established quasimesenchymal, exocrine-like, and classical subtypes based on KRT81 and CFTR immunoreactivity. CFTR protein expression was confirmed on the transcript level. CFTR and HNF1A transcript expression levels positively correlated (n=10; r=0.927; p=0.001). PDAC subtypes of the primary tumors and the corresponding organoid lines were identical for most of the cases analyzed (6/7). Treatment with chemotherapeutic drugs revealed tendencies but no significant differences regarding drug responses. Conclusions. Human PDAC organoids can be classified into known subtypes based on KRT81 and CFTR immunoreactivity. CFTR and HNF1A mRNA levels correlated well. Furthermore, subtype-specific immunoreactivity matched well between PDAC organoids and the respective primary tumor tissue. Subtyping of human PDACs using CFTR might constitute an alternative to HNF1A and should be further investigated

Integrated metabolomic, lipidomic and steroidomic profiling for revealing signatures and markers of effect induced by bisphenols exposure on human testicular function

International audienceThe Newplast research project (ANR-13-CESA-0012-01) focuses on substitutes and derivatives of bisphenol A (BPA) which are used in the manufacture of polycarbonate and epoxy resins, including food contact materials. Its global objective is to generate data and knowledge as regards (i) their biotransformation and biological impact on the human hepatic and reproductive functions, (ii) their modes of actions at molecular level through ligand-receptor binding / transactivation mechanisms and (iii) human external and internal exposure assessment. The effect of BPA and related substitutes (BPS and BPF) on testicular function was assessed on fetal (FEGA) and adult (TEXAS) models using an integrated metabolomic, lipidomic and steroidomic profiling approach. Three complementary workflows were then combined to generate a unique set of biological signatures as a support for markers of effect discovery. A rationalized sample preparation permitted to fractionate each characterized sample into one polar fraction for RPLC-ESI(+/-)-HRMS metabolomic profiling, and one apolar phase for RPLC-ESI(+/-)-HRMS lipidomic and GC-EI-MS/MS steroidomic profiling. Moreover a comprehensive characterization from both culture medium (exo-metabolome) and testicular tissue (endo-metabolome) was achieved. All together, obtained results give an extended picture of biological disruptions induced by BPA and two main substitutes (BPS and BPF) on human testicular target, including dose-responses and mixture effects. A set of annotated and particularly affected metabolites was revealed from each investigated metabolome sub-component