Total synthesis of the marine toxin phorboxazole A using palladium(II)-mediated intramolecular alkoxycarbonylation for tetrahydropyran synthesis

The potent antitumor agent phorboxazole A was synthesized from six subunits comprising C1-C2 (115), C3-C8 (98), C9-C19 (74), C20-C32 (52), C33-C41 (84) and C42-C46 (85). Tetrahydropyrans B and C containing cis-2,6-disubstitution were fabricated via palladium(II)-mediated intramolecular alkoxycarbonylation which, in the case of tetrahydropyran C, was carried out with catalytic palladium(II) and p-benzoquinone as the stoichiometric re-oxidant. Tetrahydropyran D was obtained by a stereoselective tin(IV)-catalyzed coupling of a C9 aldehyde with an allylsilane, and the C19-C20 connection was made using a completely stereoselective Wittig-Schlosser (E) olefination. Coupling of the oxazole C32 methyl substituent with the intact C33-C46 δ-lactone 3 was accompanied by elimination of the vinyl bromide to a terminal alkyne, but the C32-C33 linkage was implemented successfully with 83 and C33-C41 lactone 84. The C42-C46 segment of the side chain was then appended via Julia-Kocienski olefination. The macrolide portion of phorboxazole A was completed by means of an Ando-Still-Gennari intramolecular (Z)-selective olefination at C2-C3 which required placement of a (dimethoxyphosphinyl)acetate moiety at C24. Final deprotection led to phorboxazole A via a route in which the longest linear sequence is 37 steps and the overall yield is 0.36%.This is the author's peer-reviewed final manuscript, as accepted by the publisher. The published article is copyrighted by the Royal Society of Chemistry and can be found at: http://pubs.rsc.org/en/journals/journalissues/ob

Exact soluble two-dimensional charged wormhole

We present an exactly soluble charged wormhole model in two dimensions by adding infalling chiral fermions on the static wormhole. The infalling energy due to the infalling charged matter requires the classical back reaction of the geometry, which is solved by taking into account of the nontrivial nonchiral exotic energy. Finally, we obtain the exact expression for the size of the throat depending on the total amount of the infalling net energy and discuss the interesting transition from the AdS spacetime to the wormhole geometry.Comment: 8 pages, no figure

A Conserved Bicycle Model for Circadian Clock Control of Membrane Excitability

SummaryCircadian clocks regulate membrane excitability in master pacemaker neurons to control daily rhythms of sleep and wake. Here, we find that two distinctly timed electrical drives collaborate to impose rhythmicity on Drosophila clock neurons. In the morning, a voltage-independent sodium conductance via the NA/NALCN ion channel depolarizes these neurons. This current is driven by the rhythmic expression of NCA localization factor-1, linking the molecular clock to ion channel function. In the evening, basal potassium currents peak to silence clock neurons. Remarkably, daily antiphase cycles of sodium and potassium currents also drive mouse clock neuron rhythms. Thus, we reveal an evolutionarily ancient strategy for the neural mechanisms that govern daily sleep and wake

A peptide corresponding to the neuropilin-1-binding site on VEGF165 induces apoptosis of neuropilin-1-expressing breast tumour cells

There is increasing evidence that vascular endothelial growth factor (VEGF) has autocrine as well as paracrine functions in tumour biology. Vascular endothelial growth factor-mediated cell survival signalling occurs via the classical tyrosine kinase receptors Flt-1, KDR/Flk-1 and the more novel neuropilin (NP) receptors, NP-1 and NP-2. A 24-mer peptide, which binds to neuropilin-1, induced apoptosis of murine and human breast carcinoma cells, whereas a peptide directed against KDR had no effect. Both anti-NP1 and anti-KDR peptides induced endothelial cell apoptosis. Confocal microscopy using 5-(6)-carboxyfluorescein-labelled peptides showed that anti-NP1 bound to both tumour and endothelial cells, whereas anti-KDR bound endothelial cells only. This study demonstrates that NP-1 plays an essential role in autocrine antiapoptotic signalling by VEGF in tumour cells and that NP1-blockade induces tumour cell and endothelial cell apoptosis. Specific peptides can therefore be used to target both autocrine (tumour cells) and paracrine (endothelial cells) signalling by VEGF

Expression of TLR2, TLR4, and TLR9 in dermatomyositis and polymyositis

The aim of this study was to investigate the expressions of Toll-like receptor (TLR) 2, TLR4, TLR9, and their correlations with the expression of cytokines that are associated with activation of CD4+ T cells and inflammation including interferon γ (IFNγ), interleukin 4 (IL4), interleukin 17 (IL17), and tumor necrosis factor α (TNFα) in muscle tissues of patients with dermatomyositis (DM) and polymyositis (PM). The expressions of TLR2, TLR4, TLR9, IFNγ, IL4, IL17, and TNFα were measured by real-time reverse transcription–polymerase chain reaction in muscle tissues from 14 patients with DM and PM (nine patients with DM, five patients with PM) and three controls. The expressions of TLR2, TLR4, and TLR9 were also localized with immunohistochemistry. The expression levels of TLR2, TLR4, TLR9, IFNγ, IL4, IL17, and TNFα were significantly high in patients with DM and PM compared with those in the controls, and the expression levels of TLR4 and TLR9 had significant positive correlations with the expressions of IFNγ, IL4, IL17, and TNFα. Immunohistochemistry showed that TLR2, TLR4, and TLR9 were expressed by infiltrating cells of perimysium in DM, whereas they were expressed by infiltrating cells of endomysium in PM. These results suggest that the involvement of TLR4 and TLR9 in immunopathogenesis of DM and PM might be connected with activation of CD4+ T cells

Intracerebroventricular injection of human umbilical cord blood mesenchymal stem cells in patients with Alzheimer’s disease dementia: a phase I clinical trial

Backgrounds: Alzheimer's disease is the most common cause of dementia, and currently, there is no disease-modifying treatment. Favorable functional outcomes and reduction of amyloid levels were observed following transplantation of mesenchymal stem cells (MSCs) in animal studies. Objectives: We conducted a phase I clinical trial in nine patients with mild-to-moderate Alzheimer's disease dementia to evaluate the safety and dose-limiting toxicity of three repeated intracerebroventricular injections of human umbilical cord blood-derived MSCs (hUCB-MSCs). Methods: We recruited nine mild-to-moderate Alzheimer's disease dementia patients from Samsung Medical Center, Seoul, Republic of Korea. Four weeks prior to MSC administration, the Ommaya reservoir was implanted into the right lateral ventricle of the patients. Three patients received a low dose (1.0 × 107 cells/2 mL), and six patients received a high dose (3.0 × 107 cells/2 mL) of hUCB-MSCs. Three repeated injections of MSCs were performed (4-week intervals) in all nine patients. These patients were followed up to 12 weeks after the first hUCB-MSC injection and an additional 36 months in the extended observation study. Results: After hUCB-MSC injection, the most common adverse event was fever (n = 9) followed by headache (n = 7), nausea (n = 5), and vomiting (n = 4), which all subsided within 36 h. There were three serious adverse events in two participants that were considered to have arisen from the investigational product. Fever in a low dose participant and nausea with vomiting in another low dose participant each required extended hospitalization by a day. There were no dose-limiting toxicities. Five participants completed the 36-month extended observation study, and no further serious adverse events were observed. Conclusions: Three repeated administrations of hUCB-MSCs into the lateral ventricle via an Ommaya reservoir were feasible, relatively and sufficiently safe, and well-tolerated. Currently, we are undergoing an extended follow-up study for those who participated in a phase IIa trial where upon completion, we hope to gain a deeper understanding of the clinical efficacy of MSC AD therapy

Hybrid integrated photomedical devices for wearable vital sign tracking

In light of the importance of and challenges inherent in realizing a wearable healthcare platform for simultaneously recognizing, preventing, and treating diseases while tracking vital signs, the development of simple and customized functional devices has been required. Here, we suggest a new approach to make a stretchable light waveguide which can be combined with integrated functional devices, such as organic photodetectors and nanowire-based heaters, for multifunctional healthcare monitoring. Controlling the reflection condition of the medium gave us a solid design rule for strong light emission in our stretchable waveguides. Based on this rule, the stretchable light waveguide (up to 50% strain) made of polydimethylsiloxane was successfully demonstrated with strong emissions. We also incorporated highly sensitive organic photodetectors and silver nanowire-based heaters with the stretchable waveguide for the detection of vital signs, including heart rate, deep breathing, coughs, and blood oxygen saturation. Through these multifunctional performances, we have successfully demonstrated that our stretchable light waveguide has a strong potential for multifunctional healthcare monitoring

ALMA ACA and Nobeyama Observations of Two Orion Cores in Deuterated Molecular Lines

We mapped two molecular cloud cores in the Orion A cloud with the 7 m Array of the Atacama Compact Array (ACA) of the Atacama Large Millimeter/submillimeterArray (ALMA) and with the Nobeyama 45 m radio telescope. These cores have bright N2D+ emission in single-pointing observations with the Nobeyama 45 m radio telescope, have a relatively high deuterium fraction, and are thought to be close to the onset of star formation. One is a star-forming core, and the other is starless. These cores are located along filaments observed in N2H+ and show narrow line widths of 0.41 km s(-1) and 0.45 km s(-1) in N2D+, respectively, with the Nobeyama 45 m telescope. Both cores were detected with the ALMA ACA 7 m Array in the continuum and molecular lines at Band 6. The starless core G211 shows a clumpy structure with several sub-cores, which in turn show chemical differences. Also, the sub-cores in G211 have internal motions that are almost purely thermal. The starless sub-core G211D, in particular, shows a hint of the inverse P Cygni profile, suggesting infall motion. The star-forming core G210 shows an interesting spatial feature of two N2D+ peaks of similar intensity and radial velocity located symmetrically with respect to the single dust continuum peak. One interpretation is that the two N2D+ peaks represent an edge-on pseudo-disk. The CO outflow lobes, however, are not directed perpendicular to the line connecting both N2D+ peaks.Peer reviewe

Platinum Assisted Vapor–Liquid–Solid Growth of Er–Si Nanowires and Their Optical Properties

We report the optical activation of erbium coated silicon nanowires (Er–SiNWs) grown with the assist of platinum (Pt) and gold (Au), respectively. The NWs were grown on Si substrates by using a chemical vapor transport process using SiCl4 and ErCl4 as precursors. Pt as well as Au worked successfully as vapor–liquid–solid (VLS) catalysts for growing SiNWs with diameters of ~100 nm and length of several micrometers, respectively. The SiNWs have core–shell structures where the Er-crystalline layer is sandwiched between silica layers. Photoluminescence spectra analyses showed the optical activity of SiNWs from both Pt and Au. A stronger Er3+ luminescence of 1,534 nm was observed from the SiNWs with Pt at room- and low-temperature (25 K) using the 488- and/or 477-nm line of an Ar laser that may be due to the uniform incorporation of more Er ions into NWs with the exclusion of the formation of catalyst-induced deep levels in the band-gap. Pt would be used as a VLS catalyst for high performance optically active Er–SiNWs

Molecular Cloud Cores with a High Deuterium Fraction : Nobeyama Single-pointing Survey

We present the results of a single-pointing survey of 207 dense cores embedded in Planck Galactic Cold Clumps distributed in five different environments (lambda Orionis, Orion A, Orion B, the Galactic plane, and high latitudes) to identify dense cores on the verge of star formation for the study of the initial conditions of star formation. We observed these cores in eight molecular lines at 76-94 GHz using the Nobeyama 45 m telescope. We find that early-type molecules (e.g., CCS) have low detection rates and that late-type molecules (e.g., N(2)H(+)and c-C3H2) and deuterated molecules (e.g., N(2)D(+)and DNC) have high detection rates, suggesting that most of the cores are chemically evolved. The deuterium fraction (D/H) is found to decrease with increasing distance, indicating that it suffers from differential beam dilution between the D/H pair of lines for distant cores (>1 kpc). For lambda Orionis, Orion A, and Orion B located at similar distances, D/H is not significantly different, suggesting that there is no systematic difference in the observed chemical properties among these three regions. We identify at least eight high-D/H cores in the Orion region and two at high latitudes, which are most likely to be close to the onset of star formation. There is no clear evidence of the evolutionary change in turbulence during the starless phase, suggesting that the dissipation of turbulence is not a major mechanism for the beginning of star formation as judged from observations with a beam size of 0.04 pc.Peer reviewe