Absence of integrin-mediated TGFβ1 activation in vivo recapitulates the phenotype of TGFβ1-null mice

The multifunctional cytokine transforming growth factor (TGF) β1 is secreted in a latent complex with its processed propeptide (latency-associated peptide [LAP]). TGFβ1 must be functionally released from this complex before it can engage TGFβ receptors. One mechanism of latent TGFβ1 activation involves interaction of the integrins αvβ6 and αvβ8 with an RGD sequence in LAP; other putative latent TGFβ1 activators include thrombospondin-1, oxidants, and various proteases. To assess the contribution of RGD-binding integrins to TGFβ1 activation in vivo, we created a mutation in Tgfb1 encoding a nonfunctional variant of the RGD sequence (RGE). Mice with this mutation (Tgfb1RGE/RGE) display the major features of Tgfb1−/− mice (vasculogenesis defects, multiorgan inflammation, and lack of Langerhans cells) despite production of normal levels of latent TGFβ1. These findings indicate that RGD-binding integrins are requisite latent TGFβ1 activators during development and in the immune system

Molecular Signatures of the Primitive Prostate Stem Cell Niche Reveal Novel Mesenchymal-Epithelial Signaling Pathways

Signals between stem cells and stroma are important in establishing the stem cell niche. However, very little is known about the regulation of any mammalian stem cell niche as pure isolates of stem cells and their adjacent mesenchyme are not readily available. The prostate offers a unique model to study signals between stem cells and their adjacent stroma as in the embryonic prostate stem cell niche, the urogenital sinus mesenchyme is easily separated from the epithelial stem cells. Here we investigate the distinctive molecular signals of these two stem cell compartments in a mammalian system.We isolated fetal murine urogenital sinus epithelium and urogenital sinus mesenchyme and determined their differentially expressed genes. To distinguish transcripts that are shared by other developing epithelial/mesenchymal compartments from those that pertain to the prostate stem cell niche, we also determined the global gene expression of epidermis and dermis of the same embryos. Our analysis indicates that several of the key transcriptional components that are predicted to be active in the embryonic prostate stem cell niche regulate processes such as self-renewal (e.g., E2f and Ap2), lipid metabolism (e.g., Srebp1) and cell migration (e.g., Areb6 and Rreb1). Several of the enriched promoter binding motifs are shared between the prostate epithelial/mesenchymal compartments and their epidermis/dermis counterparts, indicating their likely relevance in epithelial/mesenchymal signaling in primitive cellular compartments. Based on differential gene expression we also defined ligand-receptor interactions that may be part of the molecular interplay of the embryonic prostate stem cell niche.We provide a comprehensive description of the transcriptional program of the major regulators that are likely to control the cellular interactions in the embryonic prostatic stem cell niche, many of which may be common to mammalian niches in general. This study provides a comprehensive source for further studies of mesenchymal/epithelial interactions in the prostate stem cell niche. The elucidation of pathways in the normal primitive niche may provide greater insight into mechanisms subverted during abnormal proliferative and oncogenic processes. Understanding these events may result in the development of specific targeted therapies for prostatic diseases such as benign prostatic hypertrophy and carcinomas

Molecular Signatures of Prostate Stem Cells Reveal Novel Signaling Pathways and Provide Insights into Prostate Cancer

BACKGROUND:The global gene expression profiles of adult and fetal murine prostate stem cells were determined to define common and unique regulators whose misexpression might play a role in the development of prostate cancer. METHODOLOGY/PRINCIPAL FINDINGS:A distinctive core of transcriptional regulators common to both fetal and adult primitive prostate cells was identified as well as molecules that are exclusive to each population. Elements common to fetal and adult prostate stem cells include expression profiles of Wnt, Shh and other pathways identified in stem cells of other organs, signatures of the aryl-hydrocarbon receptor, and up-regulation of components of the aldehyde dehydrogenase/retinoic acid receptor axis. There is also a significant lipid metabolism signature, marked by overexpression of lipid metabolizing enzymes and the presence of the binding motif for Srebp1. The fetal stem cell population, characterized by more rapid proliferation and self-renewal, expresses regulators of the cell cycle, such as E2f, Nfy, Tead2 and Ap2, at elevated levels, while adult stem cells show a signature in which TGF-beta has a prominent role. Finally, comparison of the signatures of primitive prostate cells with previously described profiles of human prostate tumors identified stem cell molecules and pathways with deregulated expression in prostate tumors including chromatin modifiers and the oncogene, Erg. CONCLUSIONS/SIGNIFICANCE:Our data indicate that adult prostate stem or progenitor cells may acquire characteristics of self-renewing primitive fetal prostate cells during oncogenesis and suggest that aberrant activation of components of prostate stem cell pathways may contribute to the development of prostate tumors

Tceal7 Regulates Skeletal Muscle Development through Its Interaction with Cdk1

We have previously reported Tceal7 as a muscle-specific gene that represses myoblast proliferation and promotes myogenic differentiation. The regulatory mechanism of Tceal7 gene expression has been well clarified recently. However, the underlying mechanism of Tceal7 function in skeletal muscle development remains to be elucidated. In the present study, we have generated an MCK 6.5 kb-HA-Tceal7 transgenic model. The transgenic mice are born normally, while they have displayed defects in the growth of body weight and skeletal muscle myofiber during postnatal development. Although four RxL motifs have been identified in the Tceal7 protein sequence, we have not detected any direct protein-protein interaction between Tceal7 and Cyclin A2, Cyclin B1, Cylin D1, or Cyclin E1. Further analysis has revealed the interaction between Tceal7 and Cdk1 instead of Cdk2, Cdk4, or Cdk6. Transgenic overexpression of Tceal7 reduces phosphorylation of 4E-BP1 Ser65, p70S6K1 Thr389, and Cdk substrates in skeletal muscle. In summary, these studies have revealed a novel mechanism of Tceal7 in skeletal muscle development

Analysis of triple-band binary metamaterial absorber based on low-permittivity all-dielectric resonance surface

Different from the conventional metamaterial absorbers (MAs), which used metal resonance surface and ternary structure (metal–dielectric-backplane), as an alternative route, the all-dielectric resonance surface (ADRS) made of single low-permittivity dielectric is proposed to design binary (dielectric backplane) metamaterial absorber (BMA). As an illustration, a triple-band BMA composed of ADRS with a metallic backplane is designed and fabricated, where the ADRS incorporates two dielectric layers with different hole-array structures. The absorbing mechanisms of this kind of absorber are analyzed via analyzing configurations of power loss density, electric field and magnetic field, as well as investigating dependences of absorbing properties on structure dimensions. The study indicates that the structural design of ADRS leads to reverse magnetic field rings distributed inside the dielectric, forming the strong couplings at the resonance frequencies. The proposed BMA relies on low-permittivity ADRS, with the rapid preparation and low cost greatly simplifying the design of MAs. The current concept is also suitable to design multi-band and broadband MAs worked at other bands, by changing the structural design of ADRS

Transcription Regulation of <i>Tceal7</i> by the Triple Complex of Mef2c, Creb1 and Myod

Tceal7 has been identified as a direct, downstream target gene of MRF in the skeletal muscle. The overexpression of Tceal7 represses myogenic proliferation and promotes cell differentiation. Previous studies have defined the 0.7 kb upstream fragment of the Tceal7 gene. In the present study, we have further determined two clusters of transcription factor-binding motifs in the 0.7 kb promoter: CRE#2–E#1–CRE#1 in the proximal region and Mef2#3–CRE#3–E#4 in the distal region. Utilizing transcription assays, we have also shown that the reporter containing the Mef2#3–CRE#3–E#4 motifs is synergistically transactivated by Mef2c and Creb1. Further studies have mapped out the protein–protein interaction between Mef2c and Creb1. In summary, our present studies support the notion that the triple complex of Mef2c, Creb1 and Myod interacts with the Mef2#3–CRE#3–E#4 motifs in the distal region of the Tceal7 promoter, thereby driving Tceal7 expression during skeletal muscle development and regeneration

Controlling the Thickness of Thermally Expanded Films of Graphene Oxide

&quot;Paper-like&quot; film material made from stacked and overlapping graphene oxide sheets can be exfoliated (expanded) through rapid heating, and this has until now been done with no control of the final geometry of the expanded graphene oxide material, i.e., the expansion has been physically unconstrained. (As a consequence of the heating and exfoliation, the graphene oxide is &quot;reduced&quot;, i.e., the graphene oxide platelets are deoxygenated to a degree.) We have used a confined space to constrain the expanding films to a controllable and uniform thickness. By changing the gap above the film, the final thickness of expanded films prepared from, e.g., a 10 mu m-thick graphene oxide film, could be controlled to values such as 20, 30, 50, or 100 mu m. When the expansion of the films was unconstrained, the final film was broken into pieces or had many cracks. In contrast, when the expansion was constrained, it never cracked or broke. Hot pressing the expanded reduced graphene oxide films at 1000 degrees C yielded a highly compact structure and promoted graphitization. Such thickness-controlled expansion of graphene oxide films up to tens or hundreds of times the original film thickness was used to emboss patterns on the films to produce areas with different thicknesses that remain connected &quot;in plane&quot;. In another set of experiments, we treated the original graphene oxide film with NaOH before its controlled expansion resulted in a different structure featuring uniformly distributed pores and interconnected layers as well as simultaneous activation of the carbon.clos