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The adaptive immune system generates a specific response to a vast spectrum of antigens. This remarkable property is achieved by lymphocytes that each express single and unique antigen receptors. During lymphocyte development, antigen receptor coding elements are assembled from widely dispersed gene segments. The assembly of antigen receptors is controlled at multiple levels, including epigenetic...
Many inducible genes are transcribed in bursts. In this issue, Degenhardt et al. (2009) report computational models that predict and validate patterns of stochastic gene expression.
Human breast tumors contain a breast cancer stem cell (BCSC) population with properties reminiscent of normal stem cells. We found 37 microRNAs that were differentially expressed between human BCSCs and nontumorigenic cancer cells. Three clusters, miR-200c-141, miR-200b-200a-429, and miR-183-96-182 were downregulated in human BCSCs, normal human and murine mammary stem/progenitor cells, and embryonal...
The endoplasmic reticulum (ER) consists of tubules that are shaped by the reticulons and DP1/Yop1p, but how the tubules form an interconnected network is unknown. Here, we show that mammalian atlastins, which are dynamin-like, integral membrane GTPases, interact with the tubule-shaping proteins. The atlastins localize to the tubular ER and are required for proper network formation in vivo and in vitro...
During endoplasmic reticulum (ER) stress, homeostatic signaling through the unfolded protein response (UPR) augments ER protein-folding capacity. If homeostasis is not restored, the UPR triggers apoptosis. We found that the ER transmembrane kinase/endoribonuclease (RNase) IRE1α is a key component of this apoptotic switch. ER stress induces IRE1α kinase autophosphorylation, activating the RNase to...
We have previously reported that the loss of Arx and/or Pax4 gene activity leads to a shift in the fate of the different endocrine cell subtypes in the mouse pancreas, without affecting the total endocrine cell numbers. Here, we conditionally and ectopically express Pax4 using different cell-specific promoters and demonstrate that Pax4 forces endocrine precursor cells, as well as mature α cells, to...
In animal and plant cells, mitotic chromatin locally generates microtubules that self-organize into a mitotic spindle, and its dimensions and bipolar symmetry are essential for accurate chromosome segregation. By immobilizing microscopic chromatin-coated beads on slide surfaces using a microprinting technique, we have examined the effect of chromatin on the dimensions and symmetry of spindles in Xenopus...
This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the authors. In this paper we used computational approaches to show that transcriptional cycling, i.e., periodic assembly of transcription factors and their cofactors and the resulting cyclical accumulation of mRNA, may...
Modulation of intracellular chloride concentration ([Cl − ] i ) plays a fundamental role in cell volume regulation and neuronal response to GABA. Cl − exit via K-Cl cotransporters (KCCs) is a major determinant of [Cl − ] I ; however, mechanisms governing KCC activities are poorly understood. We identified two sites in KCC3 that are rapidly dephosphorylated in...
The global financial crisis has hit biotech companies hard both in the US and Europe as venture capital dries up. Finding new sources of long-term financing for translating research into new therapeutics will be essential for maintaining innovation and new drug development by biotech companies.
Research on microbe-host interactions focuses principally on pathogens, yet our immune system must deal with the huge number of beneficial commensal bacteria in our gut. It is becoming clear that the host immune system must reach a delicate balance between destroying dangerous bacterial pathogens while preserving the beneficial gut microbiota.
Microbial DNA in the cytosol induces production of interferon-β (IFN-β) and an innate immune response. Chiu et al. (2009) now implicate cytosolic DNA-dependent RNA polymerase III as the DNA sensor linking DNA release by pathogenic bacteria and viruses in the host cell cytosol to IFN-β production and innate immunity.
Type I interferons (IFNs) are important for antiviral and autoimmune responses. Retinoic acid-induced gene I (RIG-I) and mitochondrial antiviral signaling (MAVS) proteins mediate IFN production in response to cytosolic double-stranded RNA or single-stranded RNA containing 5′-triphosphate (5′-ppp). Cytosolic B form double-stranded DNA, such as poly(dA-dT)•poly(dA-dT) [poly(dA-dT)], can also induce...
The nuclear receptor PPARα is activated by drugs to treat human disorders of lipid metabolism. Its endogenous ligand is unknown. PPARα-dependent gene expression is impaired with inactivation of fatty acid synthase (FAS), suggesting that FAS is involved in generation of a PPARα ligand. Here we demonstrate the FAS-dependent presence of a phospholipid bound to PPARα isolated from mouse liver. Binding...
Understanding the origins of insulin-producing beta cells of the pancreas could lead to new treatments for diabetes. Collombat et al. (2009) now show that in response to injury, a population of pancreatic progenitor cells can give rise to glucagon-expressing alpha cells that then transdifferentiate into beta cells.
A new study by Shimono et al. (2009) demonstrates that certain microRNAs that regulate the self-renewal factor BMI1 are downregulated in purified populations of normal mammary epithelial stem cells and breast tumor-initiating cells. These findings have important implications for the regulation of self-renewal and differentiation by microRNAs and suggest new ways of targeting cancer stem cells.
Telomeres are thought to be maintained by the preferential recruitment of telomerase to the shortest telomeres. The extension of the G-rich telomeric strand by telomerase is also believed to be coordinated with the complementary synthesis of the C strand by the conventional replication machinery. However, we show that under telomere length-maintenance conditions in cancer cells, human telomerase extends...
Myosin VI is the only known molecular motor that moves toward the minus ends of actin filaments; thus, it plays unique roles in diverse cellular processes. The processive walking of myosin VI on actin filaments requires dimerization of the motor, but the protein can also function as a nonprocessive monomer. The molecular mechanism governing the monomer-dimer conversion is not clear. We report the...
SH2 domain-mediated interactions represent a crucial step in transmembrane signaling by receptor tyrosine kinases. SH2 domains recognize phosphotyrosine (pY) in the context of particular sequence motifs in receptor phosphorylation sites. However, the modest binding affinity of SH2 domains to pY containing peptides may not account for and likely represents an oversimplified mechanism for regulation...
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