Structure of human steroid 5[alpha]-reductase 2 with the anti-androgen drug finasteride
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Xiao, Qingpin↗
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Results for “Alpha 5”
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Synthesis of 3,5-alpha-dichloro-3,5-seco-A- norcholestane
Synthesis of alpha-dichloro-seco-A-norcholestane from diol monoacetate reaction with triphenylphosphine followed by hydrolysis and repeated chlorination
Bayless, A.↗
Sterols of a contemporary lacustrine sediment
Results are reported for detailed sterol analyses of several depths (corresponding to between zero and about 150 yr in age) in a contemporary lacustrine sediment from a freshwater lake of postglacial origin in England. Delta 5-, delta 22-, and delta 5,22-sterols are identified along with 5 alpha- and 5 beta-stanols as well as a C26 stanol with a C7 side chain. Solvent extraction yields carbon number distributions for the 5 alpha- and 5 beta-stanol sediment constituents that parallel the corresponding delta 5-sterol distributions. The amounts of 5 alpha-stanols are found to exceed those of 5 beta-stanols in the sediment, and variations in the ratio of 5 alpha- to 5 beta-stanol between sediment samples from similar depths are shown to suggest an inhomogeneity of the sediment. It is found that the sterol composition of sediment cores varies markedly with depth, reflecting both the effects of a sterol hydrogenation process and a changing input to the sediment. It is concluded that C29 sterols, of probable higher-plant origin, predominate at lower sediment depths while C27 sterols, possibly derived from autochthonous sources, are more abundant in the surface sediment.
Gaskell, S. J.↗
Probing transmembrane mechanical coupling and cytomechanics using magnetic twisting cytometry
We recently developed a magnetic twisting cytometry technique that allows us to apply controlled mechanical stresses to specific cell surface receptors using ligand-coated ferromagnetic microbeads and to simultaneously measure the mechanical response in living cells. Using this technique, we have previously shown the following: (i) beta 1 integrin receptors mediate mechanical force transfer across the cell surface and to the cytoskeleton, whereas other transmembrane receptors (e.g., scavenger receptors) do not; (ii) cytoskeletal stiffness increases in direct proportion to the level of stress applied to integrins; and (iii) the slope of this linear stiffening response differs depending on the shape of the cell. We now show that different integrins (beta 1, alpha V beta 3, alpha V, alpha 5, alpha 2) and other transmembrane receptors (scavenger receptor, platelet endothelial cell adhesion molecule) differ in their ability to mediate force transfer across the cell surface. In addition, the linear stiffening behavior previously observed in endothelial cells was found to be shared by other cell types. Finally, we demonstrate that dynamic changes in cell shape that occur during both cell spreading and retraction are accompanied by coordinate changes in cytoskeletal stiffness. Taken together, these results suggest that the magnetic twisting cytometry technique may be a powerful and versatile tool for studies analyzing the molecular basis of transmembrane mechanical coupling to the cytoskeleton as well as dynamic relations between changes in cytoskeletal structure and alterations in cell form and function.
NASA Discipline Number 40-20↗
Interpretation of the Mariner 5 Lyman alpha measurements.
Mariner 5 Lyman alpha measurements fitted with barometric-exospheric equation using two component model atmosphere
Barth, C. A.↗
Analysis of two-dimensional incompressible flow past airfoils using unsteady Navier-Stokes equations
The conservative form of the unsteady Navier-Stokes equations in terms of vorticity and stream function in generalized curvilinear coordinates are used to analyze the flow structure of steady separation and unsteady flow with massive separation. The numerical method solves the discretized equations using an ADI-BGE method. The method is applied to a symmetric 12 percent thick Joukowski airfoil. A conformal clustered grid is generated; several 1-D stretching transformations are used to obtain a grid that attempts to resolve many of the multiple scales of the unsteady flow with massive separation, while maintaining the transformation metrics to be smooth and continuous in the entire flow field. Detailed numerical results are obtained for three flow configurations (1) Re = 1000, alpha = 5 deg, (2) Re = 1000, alpha = 15 deg, (3) Re = 10,000, alpha = 5 deg. No artificial dissipation was added; however, lack of a fine grid in the normal direction has presently led to results which are considered qualitative, especially for case (3).
Ghia, K. N.↗
Analysis of two-dimensional incompressible flow past airfoils using unsteady Navier-Stokes equations
The conservative form of the unsteady Navier-Stokes equations in terms of vorticity and stream function in generalized curvilinear coordinates are used to analyze the flow structure of steady separation and unsteady flow with massive separation. The numerical method solves the discretized equations using an ADI-BGE method. The method is applied to a symmetric 12 percent thick Joukowski airfoil. A conformal clustered grid is generated; several 1-D stretching transformations are used to obtain a grid that attempts to resolve many of the multiple scales of the unsteady flow with massive separation, while maintaining the transformation metrics to be smooth and continuous in the entire flow field. Detailed numerical results are obtained for three flow configurations (1) Re = 1000, alpha = 5 deg., (2) Re =1000, alpha = 15 deg., (3) Re = 10,000, alpha = 5 deg. No artificial dissipation was added; however, lack of a fine grid in the normal direction has presently led to results which are considered qualitative, especially for case (3).
Ghia, K. N.↗
GABAA receptor subunit gene expression in human prefrontal cortex: comparison of schizophrenics and controls
The prefrontal cortex of schizophrenics is hypoactive and displays changes related to inhibitory, GABAergic neurons, and GABAergic synapses. These changes include decreased levels of glutamic acid decarboxylase (GAD), the enzyme for GABA synthesis, upregulation of muscimol binding, and downregulation of benzodiazepine binding to GABAA receptors. Studies in the visual cortex of nonhuman primates have demonstrated that gene expression for GAD and for several GABAA receptor subunit polypeptides is under control of neuronal activity, raising the possibility that similar mechanisms in the hypoactive prefrontal cortex of schizophrenics may explain the abnormalities in GAD and in GABAA receptor regulation. In the present study, which is the first of its type on human cerebral cortex, levels of mRNAs for six GABAA receptor subunits (alpha 1, alpha 2, alpha 5, beta 1, beta 2, gamma 2) and their laminar expression patterns were analyzed in the prefrontal cortex of schizophrenics and matched controls, using in situ hybridization histochemistry and densitometry. Three types of laminar expression pattern were observed: mRNAs for the alpha 1, beta 2, and gamma 2 subunits, which are the predominant receptor subunits expressed in the mature cortex, were expressed at comparatively high levels by cells of all six cortical layers, but most intensely by cells in lower layer III and layer IV. mRNAs for the alpha 2, alpha 5, and beta 1 subunits were expressed at lower levels; alpha 2 and beta 1 were expressed predominantly by cells in layers II, III, and IV; alpha 5 was expressed predominantly in layers IV, V, and VI. There were no significant changes in overall mRNA levels for any of the receptor subunits in the prefrontal cortex of schizophrenics, and the laminar expression pattern of all six receptor subunit mRNAs did not differ between schizophrenics and controls. Because gene expression for GABAA receptor subunits is not consistently altered in the prefrontal cortex of schizophrenics, the previously reported upregulation of muscimol binding sites and downregulation of benzodiazepine binding sites in the prefrontal and adjacent cingulate cortex of schizophrenics are possibly due to posttranscriptional modifications of mRNAs and their translated polypeptides.
NASA Discipline Neuroscience↗
Regulation of Osteoblast Survival by the Extracellular Matrix and Gravity
Spaceflight adversely affects the skeleton, posing a substantial risk to astronaut's health during long duration missions. The reduced bone mass observed in growing animals following spaceflight is due at least in part to inadequate bone formation by osteoblasts. Thus, it is of central importance to identify basic cellular mechanisms underlying normal bone formation. The fundamental ideas underlying our research are that interactions between extracellular matrix proteins, integrin adhesion receptors, cytoplasmic signaling and cytoskeletal proteins are key ingredients for the proper functioning of osteoblasts, and that gravity impacts these interactions. As an in vitro model system we used primary fetal rat calvarial cells which faithfully recapitulate osteoblast differentiation characteristically observed in vivo. We showed that specific integrin receptors ((alpha)3(beta)1), ((alpha)5(beta)1), ((alpha)8(betal)1) and extracellular matrix proteins (fibronectin, laminin) were needed for the differentiation of immature osteoblasts. In the course of maturation, cultured osteoblasts switched from depending on fibronectin and laminin for differentiation to depending on these proteins for their very survival. Furthermore, we found that manipulating the gravity vector using ground-based models resulted in activation of key intracellular survival signals generated by integrin/extracellular matrix interactions. We are currently testing the in vivo relevance of some of these observations using targeted transgenic technology. In conclusion, mechanical factors including gravity may participate in regulating survival via cellular interactions with the extracellular matrix. This leads us to speculate that microgravity adversely affects the survival of osteoblasts and contributes to spaceflight-induced osteoporosis.
Globus. Ruth K.↗
Integrin-extracellular matrix interactions in connective tissue remodeling and osteoblast differentiation
The differentiaton of bone cells is a complex multistep process. Bone is somewhat unusual in that it is very actively and continually remodeled in the adult and that maintenance of its mass in the mature organism is exquisitely sensitive to mechanical as well as chemical signals. Bone is also unique because it consists of a very large amount of extracellular matrix (ECM) that is mineralized. The integrin family of ECM receptors has been shown to play an important role in tissue morphogenesis in several systems. Our studies on the regulation of matrix remodeling enzymes by integrins in rabbit synovial fibroblasts show that two b1 integrin fibronectin (FN) receptor complexes (alpha 5 beta 1 and alpha 4 beta 1) cooperate in detecting subtle changes in the composition of the ECM. As a result of signal transduction by these integrins, the levels of mRNA and protein for several members of the metalloproteinase family are regulated in these cells. We have also used antibody and RGD peptide perturbation studies to determine the significance of cell/ECM interactions to normal osteogenesis. We found that interactions between the cell binding domain of FN and integrins are required for both normal morphogenesis and gene expression in cultured osteoblasts that differentiate to form bone-like tissue in culture. These data lead us to propose that beta 1 integrins play an important role in osteoblast differentiation as well as in bone remodeling.
NASA Discipline Number 26-10↗
Human α-defensin 5 suppressed colon cancer growth by targeting PI3K pathway
Defensins are highly conserved antimicrobial peptides, which ubiquitously expressed in different species. In addition to the functions in host defense, their aberrant expression have also been documented in cancerous tissue including breast cancer, lung caner and renal carcinoma etc. Whereas, roles of Defensin Alpha 5 (DEFA5) in colon cancer has not been explored. Bioinformatic analysis was used to study the expression of DEFA5 and its correlation with clinical outcomes; Western blot, qPCR, Co-immunoprecipitation, xenograft models were used to the study the molecular mechanism. Decreased expression of DEFA5 at protein level was observed in colon tissues. Colon cancer cell lines proliferation and colony formation capacity were significantly suppressed by DEFA5 overexpression. Moreover, in vivo tumor growth in nude mice was also suppressed by DEFA5 overexpression, suggesting a tumor suppressor role of DEFA5 in colon cancer. Mechanistically, DEFA5 directly binds to the subunits of PI3K complex, thus attenuates the downstream signaling transduction, leads to delayed cell growth and metastasis. Collectively, we concluded that DEFA5 showed an inhibitory effect in colon cancer cell growth and may serve as a potential tumor suppressor in colon cancer.
60 APPLIED LIFE SCIENCES↗
The ultraviolet flux envelopes of main-sequence B stars
Flux envelopes on an absolute energy scale from 1100 to 6000 A prepared from OAO-2 scans and from published ground-based material are presented for gamma Leporis, B0.5 5 eta Ursae Majoris, B3 5, gamma Ursae Majoris, A0 5, and alpha Lyrae, A0 5, and for alpha Canis Majoris Al 5 from rocket scans. These, with already published flux envelopes for Zeta Draconis, B6 3, and alpha Leonis, B7 5 (Underhill 1972) are intercompared and compared with reference flux envelopes predicted by LTE theory from lightly line-blanketed model atmospheres. A considerable line blocking occurs at wavelengths shortward of 3000 A with respect to the theoretical continuous spectra. The line blocking may be as much as 50 per cent at 1500 A and between 1500 A and 2500 A it is comparable to that which exists in the sun between 3000 A and 4000 A. Although gamma Urase Majoris, alpha Lyrae and alpha Canis Majoris have very similar visible spectra when viewed at low resolution, their ultraviolet spectra are significantly different, in particular alpha Lyrae shows an ultraviolet excess.
Underhill, A. B.↗
Surveyor 5 science results.
Surveyor 5 alpha particle backscattering instrument measurement, TV pictures of lunar surface elemental composition and magnetic and mechanical measurements
Jaffe, L. D.↗
Offset fed utilization of four quadrants of an axially symmetrical antenna structure
Theoretical calculations conducted for the use of the hoop column structure were in a quad antenna configuration. The coverage of the US 48 states by a C band Comsat system, which operates in the 3.7 - 4.2 GHz downlink and 5.925 - 6.425 GHz uplink frequency band is considered. This system provides most of its coverage toward major cities (10 or 18 spot beams) and the rest of its coverage on a contiguous basis for the remaining of the country. An alpha = .5 and .3 cell size (approximate component bandwidth) is assumed. Among the practically infinite possible beam topologies one plan for the area coverage and three plans for the spot beam coverage are analyzed.
Foldes, P.↗
Implementation of the Baldwin-Barth turbulence model into the ZETA code and its diagnosis
The Baldwin-Barth turbulence model was implemented into Zeta, a time-accurate, zonal, integro-differential code for incompressible laminar and turbulent flows. The implementation procedure is patterned after the model subroutine in ARC2D. The results of ZETA with the Baldwin-Barth turbulence model were compared with experimental data, with ZETA using Baldwin-Lomax model, and with ARC2D using the Baldwin-Barth model. The Baldwin-Barth model subroutine was tested by inputting an ARC2D velocity solution of an NACA-0012 airfoil at R(sub e) = 3.9 x 10(exp 6) and alpha = 5 deg. The resultant turbulent viscosity and Reynolds stresses compared favorably with the original data. For the same grid having grid points inside the laminar sublayer, which is necessary due to the one-equation nature of the model, ZETA however predicts early separation. It was found that the current ZETA has problem with such a fine grid. Further work is in progress to solve this problem.
Low, Scott L.↗
Fibronectin regulates calvarial osteoblast differentiation
The secretion of fibronectin by differentiating osteoblasts and its accumulation at sites of osteogenesis suggest that fibronectin participates in bone formation. To test this directly, we determined whether fibronectin-cell interactions regulate progressive differentiation of cultured fetal rat calvarial osteoblasts. Spatial distributions of alpha 5 integrin subunit, fibronectin, osteopontin (bone sialoprotein I) and osteocalcin (bone Gla-protein) were similar in fetal rat calvaria and mineralized, bone-like nodules formed by cultured osteoblasts. Addition of anti-fibronectin antibodies to cultures at confluence reduced subsequent formation of nodules to less than 10% of control values, showing that fibronectin is required for normal nodule morphogenesis. Anti-fibronectin antibodies selectively inhibited steady-state expression of mRNA for genes associated with osteoblast differentiation; mRNA levels for alkaline phosphatase and osteocalcin were suppressed, whereas fibronectin, type I collagen and osteopontin were unaffected. To identify functionally relevant domains of fibronectin, we treated cells with soluble fibronectin fragments and peptides. Cell-binding fibronectin fragments (type III repeats 6-10) containing the Arg-Gly-Asp (RGD) sequence blocked both nodule initiation and maturation, whether or not they contained a functional synergy site. In contrast, addition of the RGD-containing peptide GRGDSPK alone did not inhibit nodule initiation, although it did block nodule maturation. Thus, in addition to the RGD sequence, other features of the large cell-binding fragments contribute to the full osteogenic effects of fibronectin. Nodule formation and osteoblast differentiation resumed after anti-fibronectin antibodies or GRGDSPK peptides were omitted from the media, showing that the inhibition was reversible and the treatments were not cytotoxic. Outside the central cell-binding domain, peptides from the IIICS region and antibodies to the N terminus did not inhibit nodule formation. We conclude that osteoblasts interact with the central cell-binding domain of endogenously produced fibronectin during early stages of differentiation, and that these interactions regulate both normal morphogenesis and gene expression.
NASA Program Space Physiology and Countermeasures↗
Modulation of adhesion-dependent cAMP signaling by echistatin and alendronate
We measured intracellular cAMP levels in cells during attachment and spreading on different extracellular matrix (ECM) proteins. Increases in cAMP were observed within minutes when cells attached to fibronectin, vitronectin, and a synthetic RGD-containing fibronectin peptide (Petite 2000), but not when they adhered to another integrin alpha nu beta 3 ligand, echistatin. Because echistatin also inhibits bone resorption, we measured the effects of adding another osteoporosis inhibitor, alendronate, in this system. Alendronate inhibited the cAMP increase induced by ligands that primarily utilize integrin alpha nu beta 3 (vitronectin, Peptite 2000), but not by fibronectin which can also use integrin alpha 5 beta 1. These results show that cell adhesion to ECM can increase intracellular cAPM levels and raise the possibility that inhibitors of osteoporosis may act, in part, by preventing activation of this pathway by integrins.
NASA Discipline Number 40-20↗
Binary Black Hole Mergers in the First Advanced LIGO Observing Run
The first observational run of the Advanced LIGO detectors, from September 12, 2015 to January 19, 2016, saw the first detections of gravitational waves from binary black hole mergers. In this paper we present full results from a search for binary black hole merger signals with total masses up to 100M solar mass and detailed implications from our observations of these systems. Our search, based on general-relativistic models of gravitational wave signals from binary black hole systems, unambiguously identified two signals, GW150914 and GW151226, with a significance of greater than 5 alpha over the observing period. It also identified a third possible signal, LVT151012, with substantially lower significance, which has a 87 probability of being of astrophysical origin. We provide detailed estimates of the parameters of the observed systems. Both GW150914 and GW151226 provide an unprecedented opportunity to study the two-body motion of a compact-object binary in the large velocity, highly nonlinear regime. We do not observe any deviations from general relativity, and place improved empirical bounds on several high-order post-Newtonian coefficients. From our observations we infer stellar-mass binary black hole merger rates lying in the range 9-240 Gpc-3 yr-1. These observations are beginning to inform astrophysical predictions of binary black hole formation rates, and indicate that future observing runs of the Advanced detector network will yield many more gravitational wave detections.
Abbott, B. P.↗