Small molecule-mediated tribbles homolog 3 promotes bone formation induced by bone morphogenetic protein-2.

Although bone morphogenetic protein-2 (BMP2) has demonstrated extraordinary potential in bone formation, its clinical applications require supraphysiological milligram-level doses that increase postoperative inflammation and inappropriate adipogenesis, resulting in well-documented life-threatening cervical swelling and cyst-like bone formation. Recent promising alternative biomolecular strategies are toward promoting pro-osteogenic activity of BMP2 while simultaneously suppressing its adverse effects. Here, we demonstrated that small molecular phenamil synergized osteogenesis and bone formation with BMP2 in a rat critical size mandibular defect model. Moreover, we successfully elicited the BMP2 adverse outcomes (i.e. adipogenesis and inflammation) in the mandibular defect by applying high dose BMP2. Phenamil treatment significantly improves the quality of newly formed bone by inhibiting BMP2 induced fatty cyst-like structure and inflammatory soft-tissue swelling. The observed positive phenamil effects were associated with upregulation of tribbles homolog 3 (Trib3) that suppressed adipogenic differentiation and inflammatory responses by negatively regulating PPARγ and NF-κB transcriptional activities. Thus, use of BMP2 along with phenamil stimulation or Trib3 augmentation may be a promising strategy to improve clinical efficacy and safety of current BMP therapeutics

Enhanced Osteogenesis of Adipose-Derived Stem Cells by Regulating Bone Morphogenetic Protein Signaling Antagonists and Agonists.

UnlabelledAlthough adipose-derived stem cells (ASCs) are an attractive cell source for bone tissue engineering, direct use of ASCs alone has had limited success in the treatment of large bone defects. Although bone morphogenetic proteins (BMPs) are believed to be the most potent osteoinductive factors to promote osteogenic differentiation of ASCs, their clinical applications require supraphysiological dosage, leading to high medical burden and adverse side effects. In the present study, we demonstrated an alternative approach that can effectively complement the BMP activity to maximize the osteogenesis of ASCs without exogenous application of BMPs by regulating levels of antagonists and agonists to BMP signaling. Treatment of ASCs with the amiloride derivative phenamil, a positive regulator of BMP signaling, combined with gene manipulation to suppress the BMP antagonist noggin, significantly enhanced osteogenic differentiation of ASCs through increased BMP-Smad signaling in vitro. Furthermore, the combination approach of noggin suppression and phenamil stimulation enhanced the BMP signaling and bone repair in a mouse calvarial defect model by adding noggin knockdown ASCs to apatite-coated poly(lactic-coglycolic acid) scaffolds loaded with phenamil. These results suggest novel complementary osteoinductive strategies that could maximize activity of the BMP pathway in ASC bone repair while reducing potential adverse effects of current BMP-based therapeutics.SignificanceAlthough stem cell-based tissue engineering strategy offers a promising alternative to repair damaged bone, direct use of stem cells alone is not adequate for challenging healing environments such as in large bone defects. This study demonstrates a novel strategy to maximize bone formation pathways in osteogenic differentiation of mesenchymal stem cells and functional bone formation by combining gene manipulation with a small molecule activator toward osteogenesis. The findings indicate promising stem cell-based therapy for treating bone defects that can effectively complement or replace current osteoinductive therapeutics

Ginseng: A panacea linking East Asia and North America?

The Supplement title: The Art and Science of Traditional Medicine Part 3: The Global Impact of Traditional Medicinepostprin

DNA methylation modules in airway smooth muscle are associated with asthma severity

Abnormal DNA methylation patterns distinguish airway smooth muscle cell function in asthma and asthma severity

Bioassay-guided isolation and identification of antimicrobial compounds from thyme essential oil by means of overpressured layer chromatography, bioautography and GC-MS

A simple method is described for efficient isolation of compounds having an antibacterial effect. Two thyme (Thymus vulgaris) essential oils, obtained from the market, were chosen as prospective materials likely to feature several bioactive components when examined by thin layer chromatography coupled with direct bioautography as a screening method. The newly developed infusion overpressured layer chromatographic separation method coupled with direct bioautography assured that only the active components were isolated by means of overrun overpressured layer chromatography with online detection and fractionation. Each of the 5 collected fractions represented one of the five antimicrobial essential oil components designated at the screening. The purity and the activity of the fractions were confirmed with chromatography coupled various detection methods (UV, vanillin-sulphuric acid reagent, direct bioautography). The antibacterial components were identified with GC-MS as thymol, carvacrol, linalool, diethylphthalate, and alpha-terpineol. The oil component diethyl-phthalate is an artificial compound, used as plasticizer or detergent bases in the industry. Our results support that exploiting its flexibility and the possible hyphenations, overpressured layer chromatography is especially attractive for isolation of antimicrobial components from various matrixes

Spin-orbit torque in Pt/CoNiCo/Pt symmetric devices

Current induced magnetization switching by spin-orbit torques offers an energy-efficient means of writing information in heavy metal/ferromagnet (FM) multilayer systems. The relative contributions of field-like torques and damping-like torques to the magnetization switching induced by the electrical current are still under debate. Here, we describe a device based on a symmetric Pt/FM/Pt structure, in which we demonstrate a strong damping-like torque from the spin Hall effect and unmeasurable field-like torque from Rashba effect. The spin-orbit effective fields due to the spin Hall effect were investigated quantitatively and were found to be consistent with the switching effective fields after accounting for the switching current reduction due to thermal fluctuations from the current pulse. A non-linear dependence of deterministic switching of average Mzon the in-plane magnetic field was revealed, which could be explained and understood by micromagnetic simulation

Synthesis and biological activity of α-glucosyl C24:0 and C20:2 ceramides

a-Glucosyl ceramides 4 and 5 have been synthesised and evaluated for their ability to stimulate the activation and expansion of human iNKT cells. The key challenge in the synthesis of both target molecules was the stereoselective synthesis of the a-glycosidic linkage. Of the methods examined, glycosylation using per-TMS-protected glucosyl iodide 16 was completely a-selective and provided gram quantities of amine 11, from which a-glucosyl ceramides 4 and 5 were obtained by N-acylation. a-GlcCer 4, containing a C24 saturated acyl chain, stimulated a marked proliferation and expansion of human circulating iNKT cells in short-term cultures. a-GlcCer 5, which contains a C20 11,14-cis-diene acyl chain (C20:2),induced extremely similar levels of iNKT cell activation and expansion

Unveiling the oldest and most massive galaxies at very high redshift

(Abridged) This work explores the existence of high redshift massive galaxies unveiled with Spitzer+IRAC, but missed by conventional selection techniques based on optical and near-infrared observations. To this end, we use the multi-wavelength imaging data available for the GOODS-South field, and select a flux-limited sample from the IRAC 3.6um image to m(AB)<23.26. We confine our study to the galaxies undetected by the optical HST+ACS imaging and close to the detection limit of the K-band image (K>23.5 AB). Our selection unveiled 20 galaxies on which we performed a detailed photometric analysis. For each galaxy, we built an SED based on optical-to-8um photometry to estimate the photo-z and to derive the main galaxies physical properties. The majority of the sample sources show degenerate/bimodal solutions for the photometric redshifts (Abridged). These can either be heavily dust-enshrouded (Av~2-4) starbursts at 210^12 Lsun, or massive post-starburst galaxies in the redshift interval 4<z<9 with stellar masses of 10^11 Msun. One galaxy, the only source in our sample with both an X-ray and a 24um detection, might be an extremely massive object at z~8 detected during a post-starburst phase with concomitant QSO activity (although a lower-z solution is not excluded). Our investigation of Spitzer-selected galaxies with very red SEDs and completely undetected in the optical reveals a potential population of massive galaxies at z>4 which appear to include significant AGN emissions. These sources may be the oldest stellar systems at z~4. These, previously unrecognized, optically obscured objects might provide an important contribution to the massive-end (M>10^11 sun) of the high-z stellar mass function and they would almost double it (Abridged).Comment: Accepted for publication in Astronomy and Astrophysic

Characterization of Extragalactic 24micron Sources in the Spitzer First Look Survey

In this Letter, we present the initial characterization of extragalactic 24um sources in the Spitzer First Look Survey (FLS) by examining their counterparts at 8um and R-band. The color-color diagram of 24-to-8 vs. 24-to-0.7um is populated with 18,734 sources brighter than the 3sigma flux limit of 110uJy, over an area of 3.7sq.degrees. The 24-to-0.7um colors of these sources span almost 4 orders of magnitudes, while the 24-to-8um colors distribute at least over 2 orders of magnitudes. In addition to identifying ~30% of the total sample with infrared quiescent, mostly low redshift galaxies, we also found that: (1) 23% of the 24um sources (~1200/sq.degrees) have very red 24-to-8 and 24-to-0.7 colors and are probably infrared luminous starbursts with L(IR)>3x10^(11)Lsun at z>1. In particular, 13% of the sample (660/sq.degrees) are 24um detected only, with no detectable emission in either 8um or R-band. These sources are the candidates for being ULIRGs at z>2. (2) 2% of the sample (85/sq.degrees) have colors similar to dust reddened AGNs, like Mrk231 at z~0.6-3. (3) We anticipate that some of these sources with extremely red colors may be new types of sources, since they can not be modelled with any familiar type of spectral energy distribution. We find that 17% of the 24um sources have no detectable optical counterparts brighter than R limit of 25.5mag. Optical spectroscopy of these optical extremely faint 24um sources would be very difficult, and mid-infrared spectroscopy from the Spitzer would be critical for understanding their physical nature (Abridged).Comment: Accepted for publication in ApJ (Spitzer Special Issue