[2+2+1] cyclization of allenes.

The [2+2+1] cyclization of an alkyne, an alkene and carbon monoxide, i.e., the Pauson-Khand reaction, is one of the most powerful tools for constructing a five-membered ring. In place of the alkene or alkyne part, the use of an allene functionality has proven to make this reaction more valuable for organic synthesis. This review focuses on the origin and progress of the allenic [2+2+1] cyclocarbonylation, including the chirality transfer of the allene and its synthetic applications.

What sperm can teach us about energy production.

Mammalian sperm have evolved under strict selection pressures that have resulted in a highly polarized and efficient design. A critical component of that design is the compartmentalization of specific metabolic pathways to specific regions of the cell. Although the restricted localization of mitochondria to the midpiece is the best known example of this design, the organization of the enzymes of glycolysis along the fibrous sheath is the primary focus of this review. Evolution of variants of these metabolic enzymes has allowed them to function when tethered, enabling localized energy production that is essential for sperm motility. We close by exploring how this design might be mimicked to provide an energy-producing platform technology for applications in nanobiotechnology.

Chronomics of heart rate variability on earth and in space.

Chronomes are time structures consisting of multifrequency rhythms, elements of chaos, and trends in chaotic and rhythmic endpoints. Chronomics maps the dynamics of organisms' broad interactions with the environment near and far, rather than merely the daily routines. We introduced the chronomics of heart rate variability (HRV), characterized by a broad time structure, that includes the prominent circadians and also ultradian (notably about 8h and about 12h) and infradian (notably about-weekly, about-yearly, and about 10-yearly) changes, in addition to undergoing trends with aging. Alterations in these HRV chronomes are known to predict the presence of disease in the near future. Thus, for the health and safety of astronauts, HRV chronomes should be assessed before, during and after the mission in the International Space Station to check for any alteration. Future work should focus on how phenomena in the cosmos, including helio- and geomagnetics, can affect physiological chronomes, those of the HRV in particular.

Characterization of the mechanism of zidovudine uptake by rat conditionally immortalized syncytiotrophoblast cell line TR-TBT.

PURPOSE: To characterize the uptake mechanism of zidovudine (AZT), a nucleoside reverse transcriptase inhibitor, in syncytiotrophoblast cells using the TR-TBT 18d-1 cell line previously established by our group. MATERIALS AND METHODS: The effects of several transporter inhibitors on the initial and steady-state apical uptake of AZT by TR-TBT 18d-1 were characterized, in order to identify the transporter(s) involved. RESULTS: Initial uptake of AZT was sodium-independent and saturable; the K(m) value was about 16 microM. Nitrobenzylthioinosine (NBMPR), probenecid and cimetidine each had little effect on the saturable AZT uptake, indicating that well characterized transporters, such as organic anion transporters (OATs and OATPs), organic cation transporters (OCTs) and equilibrative nucleoside transporters (ENTs), are not involved. However, thymidine and 2'-deoxyuridine strongly inhibited AZT uptake. These results suggest that an unidentified nucleoside uptake transporter is responsible for the uptake of AZT. Cyclosporin A, Ko143 and probenecid had little effect on AZT accumulation by TR-TBT 18d-1 cells, suggesting that transporter-mediated efflux of AZT is not substantial. CONCLUSION: Our results indicate that saturable AZT uptake into TR-TBT 18d-1 is mediated by a so-far-unidentified transporter.

A new goldfish model to evaluate pharmacokinetic and pharmacodynamic effects of drugs used for motion sickness in different gravity loads.

This paper proposes a new goldfish model to predict pharmacodynamic/pharmacokinetic effects of drugs used to treat motion sickness administered in differing gravity loads. The assumption of these experiments is that the vestibular system is dominant in producing motion sickness and that the visual system is secondary or of small import in the production of motion sickness. Studies will evaluate the parameter of gravity and the contribution of vision to the role of the neurovestibular system in the initiation of motion sickness with and without pharmacologic agents. Promethazine will be studied first. A comparison of data obtained in different groups of goldfish will be done (normal vs. acutely and chronically bilaterally blinded vs. sham operated). Some fish will be bilaterally blinded 10 months prior to initiation of the experiment (designated the chronically bilaterally blinded group of goldfish) to evaluate the neuroplasticity of the nervous system and the associated return of neurovestibular function. Data will be obtained under differing gravity loads with and without a pharmacological agent for motion sickness. Experiments will differentiate pharmacological effects on vision vs. neurovestibular input to motion sickness. Comparison of data obtained in the normal fish and in acutely and chronically bilaterally blinded fish with those obtained in fish with intact and denervated otoliths will differentiate if the visual or neurovestibular system is dominant in response to altered gravity and/or drugs. Experiments will contribute to validation of the goldfish as a model for humans since plasticity of the central nervous system allows astronauts to adapt to the altered visual stimulus conditions of 0-g. Space motion sickness may occur until such an adaptation is achieved.

A new entry to oxacycles via base-catalyzed endo mode cyclization of allenyl sulfoxides and sulfones.

[reaction: see text]. Treatment of the allenyl sulfoxides and sulfones possessing a proper delta-hydroxy appendage at the C-1 position with potassium tert-butoxide effected endo mode ring closure at the sp-hybridized carbon center of the allenyl moiety to provide the five- to eight-membered oxacycles in high yields.

First total synthesis of (-)-ichthyothereol and its acetate.

The first and stereoselective total syntheses of (-)-ichthyothereol (1) and its acetate ((+)-2) were achieved by incorporation of the two chiral centers of diethyl L-tartrate. The starting diethyl L-tartrate was converted into trans-2-ethynyl-3-hydroxytetrahydropyran 14 in a stereoselective manner via the endo mode cyclization of the epoxy-alkyne derivative 12. The alcohol 12 was then transformed into (E)-iodoolefin derivative 15, which was exposed to a coupling reaction with 1-tributylstannyl-1,3,5-heptyne (19), derived from the corresponding 1-trimethylsilyl-1,3,5-heptyne (18), under Stille conditions to produce the all-carbon framework of the target natural products. Chemical modification of the coupled product 20 under conventional conditions completed the first total synthesis of (-)-ichthyothereol (1) and its acetate ((+)-2).

Co2(CO)8-mediated endo mode cyclization of epoxy-alcohol: synthesis of 2-ethynyl-3-hydroxy-2-methyltetrahydropyran and 2-ethynyl-3-hydroxy-3-methyltetrahydropyran derivatives.

Successive treatment of 4,5-epoxy-5-methyl-7-trimethylsilyl-6-heptyne-1-ol with Co2(CO)8 at 0 degrees C and a catalytic amount of BF3 x OEt2 at -78 degrees C gave the tetrahydropyran derivatives with the cobalt-complexed moiety. Similarly 4,5-epoxy-4-methyl-7-trimethylsilyl-6-heptyne-1-ol underwent ring closure under the above conditions to provide the corresponding tetrahydropyran derivatives. The preferential endo mode cyclization over the exo one was observed in these experiments.

Control of gravimorphogenesis by auxin: accumulation pattern of CS-IAA1 mRNA in cucumber seedlings grown in space and on the ground.

Cucumber (Cucumis sativus L.) seedlings grown in microgravity developed a peg on each side of the transition zone between hypocotyl and root, whereas seedlings grown in a horizontal position on the ground developed a peg on the concave side of the gravitropically bending transition zone. The morphological features of the space-grown seedlings were similar to those of seedlings grown in a vertical position on the ground with their radicles pointing down: both became two-pegged seedlings. Morphogenesis of cucumber seedlings is thus inhibited by gravity. Analysis by in-situ hybridization of an auxin-inducible gene, CS-IAA1, showed that its mRNA accumulated to a much greater extent on the lower side of the transition zone in the horizontally placed seedlings on the ground just prior to and during the initiation period of peg formation. On the other hand, when seedlings were grown in microgravity or in a vertical position on the ground, accumulation of CS-IAA1 mRNA occurred all around the transition zone. Accumulation of CS-IAA1 mRNA in horizontally grown seedlings appreciably decreased on the upper side of the transition zone and increased on the lower side upon gravistimulation, compared with the two-pegged seedlings. Application of IAA to seedlings in a horizontal position caused the development of a peg on each side of the transition zone, or a collar-like protuberance, depending on the concentration used. These results suggest that upon gravistimulation the auxin concentration on the upper side of the horizontally placed transition zone is reduced to a level below the threshold value necessary for peg formation. Space-grown seedlings of cucumber might develop two pegs symmetrically because the auxin level in the entire transition zone is maintained above the threshold. This spaceflight experiment verified for the first time that auxin does not redistribute in microgravity.

Pauson-Khand reaction of optically active 6,7-bis(tert-butyldimethylsiloxy)non-1-en-8-ynes

Treatment of (6S,7S)-7-bis(tert-butyldimethylsiloxy)non-1-en-8-ynes with dicobalt octacarbonyl gave the corresponding cobalt complex. This complex was subsequently exposed to the Pauson-Khand conditions in the presence of a promoter such as cyclohexylamine, thioanisole, methyl isopropyl sulfide, and butyl methyl sulfide ending up with the stereoselective production of the (2S,3S,6S,7S)-7-methylbicyclo[4.3.0]nonenone derivatives instead of the expected (2S,3S,7S)-bicyclo[5.3.0]decenone species.

Morphogenesis in cucumber seedlings is negatively controlled by gravity.

Seedlings of most cucurbitaceous plants develop a peg (protuberance caused by cell outgrowth) on the transition zone between the hypocotyl and root. The peg is necessary for removing the seed coat after germination. In our spaceflight experiments on the STS-95 space shuttle, Discovery, we found that cucumber (Cucumis sativus L.) seedlings grown under microgravity conditions developed two pegs symmetrically at the transition zone. Thus, cucumber seedlings potentially develop two pegs and do not require gravity for peg formation itself, but on the ground the development of one peg is suppressed in response to gravity. This may be considered as negative control of morphogenesis by gravity.

Synthesis and antiviral activity of novel anti-VZV 5-substituted uracil nucleosides with a cyclopropane sugar moiety.

A series of 5-substituted uracil nucleoside derivatives with a 1(1'S, 2'R)-[1',2'-bis(hydroxymethyl)cyclopropyl]methyl group as an acyclosugar moiety were synthesized and evaluated for their anti-herpetic activities. Among the compounds synthesized, (E)-5-halovinyluracil derivatives showed superior anti-varicella zoster virus (VZV) activity over acyclovir (ACV) but were less potent than ACV against herpes symplex virus type-1 (HSV-1). IC(50) values for the VZV Kawaguchi strain were 0.027 for Br, 0.070 for Cl, and 0.054 microg/mL for I derivatives and 3.4 microg/mL for ACV. The most potent compound, (1'S,2'R)-5-[(E)-2-bromoethenyl]-1-[[1', 2'-bis(hydroxymethyl)cycloprop-1'-yl]methyl]-2,4-(1H, 3H)-pyrimidinedione (3a), was 40-60-fold more potent than ACV against clinical isolates of VZV. It showed good oral bioavailability in rats (68.5%) and, unlike (E)-5-(2-bromovinyl)-1-beta-D-arabinofuranosyluracil (BVaraU), did not result in the release of (E)-5-(2-bromovinyl)uracil (BVU), a potent dihydropyrimidine dehydrogenase inhibitor, in plasma after oral administration.

The expansion of the hypopharynx by correction of glosso-larynx.

The width of the hypopharynx and oropharynx before and after the operation correction of glosso-larynx (CGL) was compared by cranial X-ray film. After the operation, the hyoid bone was seen to have moved downward, and the cranial bone was observed to have rotated forward. As a result, the hypopharynx and the oropharynx were expanded. Expansion of the hypopharynx resulted in the decreased resistance of flow decreased and the increased in airflow.

Functions of the uvula and Z-pharyngoplasty.

UPPP includes uvulotomy. The uvula works as the pilot for eating and swallowing. We performed an operation which left the uvula intact and opened the pharynx by Z-opening the palate, Z-pharyngoplasty (ZPP). Twenty-four patients were studied before and after ZPP. The results of the operations were satisfactory. No patients complained of symptoms after uvulectomy. As for the changes indicated by sleep monitoring, minimum SaO2 increased significantly (P = 0.0026), pulse rate decreased significantly (P = 0.0144), apnea index decreased significantly (P = 0.0392), snoring decreased (P = 0.064), and the amount of hours of sleep when SaO2 was over 95% increased (P = 0.0690) after ZPP.

Inhibition of root elongation in microgravity by an applied electric field.

Roots grown in an applied electric field demonstrate a bidirectional curvature. To further understand the nature of this response and its implications for the regulation of differential growth, we applied an electric field to roots growing in microgravity. We found that growth rates of roots in microgravity were higher than growth rates of ground controls. Immediately upon application of the electric field, root elongation was inhibited. We interpret this result as an indication that, in the absence of a gravity stimulus, the sensitivity of the root to an applied electric stimulus is increased. Further space experiments are required to determine the extent to which this sensitivity is shifted. The implications of this result are discussed in relation to gravitropic signaling and the regulation of differential cell elongation in the root.

Mechanical tensile properties of the aortic wall in the premature rat exposed to the microgravity environment during space flight for 16 days.

Under microgravity environment, blood shifts headward and thereafter decrease in volume to adapt to the environment, which could affect cardiovascular hemodynamics and their regulatory mechanisms. Baroreceptor sensitivity is known to be reduced in newborn animals and to gradually increase with development. The baroreceptor is a stretch receptor; therefore its function is closely related to the rheological properties and fine structure of the aortic wall in which the baroreceptor lies. The mechanical and histological properties could be altered under microgravity conditions in the process of development with change in circulatory function. In the present study, we investigated the mechanical tensile characteristics and histological structure of the aortic wall in the proximal thoracic aorta of premature rats bred in the microgravity environment of the space shuttle for 16 days.

Sensitivity of shuttle vector plasmid pZ189 DNA to carbon ion beams.

The sensitivity of shuttle vector plasmid pZ189 DNA to carbon ion beams was studied under dry conditions. This plasmid contains the supF gene that can be used in mutagenesis analysis. The survival curve of the plasmid had both a shoulder and exponential parts, and showed a D10 value of about 17 kGy for both Escherichia coli wild-type and DNA repair-deficient mutant (UV-sensitive) strains. Therefore, it was assumed that the excision repair system was not effective for repairing DNA lesions induced by irradiation with carbon ion beams.