bluuebunny/crossref_metadata_2025_split huggingface dataset:
Protein kinase inhibitors: contributions from structure to clinical compounds
Authors: Johnson Louise N. 
Published: March 2009

AbstractProtein kinases catalyse key phosphorylation reactions in signalling cascades that affect every aspect of cell growth, differentiation and metabolism. The kinases have become prime targets for drug intervention in the diseased state, especially in cancer. There are currently 10 drugs that have been approved for clinical use and many more in clinical trials. This review summarises the structural basis for protein kinase inhibition and discusses the mode of action for each of the approved drugs in the light of structural results. All but one of the approved compounds target the ATP binding site on the kinase. Both the active and inactive conformations of protein kinases have been used in strategies to produce potent and selective compounds. Targeting the inactive conformation can give high specificity. Targeting the active conformation is favourable where the diseased state has arisen from activating mutations, but such inhibitors generally target several protein kinases. Drug resistance mutations are a potential risk for both conformational states, where drug-binding regions are not directly involved in catalysis. Imatinib (Glivec), the most successful of protein kinase inhibitors, targets the inactive conformation of ABL tyrosine kinase. Newer compounds, such as dasatinib, which targets the ABL active state, have been developed to increase potency and have proved effective for some, but not all, drug-resistant mutations. The first epidermal growth factor receptor (EGFR) inhibitors in clinical use [gefitinib (Iressa) and erlotinib (Tarceva)] targeted the active form of the kinase, and this proved advantageous for patients whose cancer was caused by mutations that resulted in a constitutively active EGFR kinase domain. Newer approved compounds, such as lapatinib (Tykerb), target the inactive conformation with high potency. A further compound that forms a covalent attachment to the kinase has been found to overcome one of the major drug resistance mutations, where the effectiveness of the drugin vivois dependent on its ability to compete successfully in the presence of cellular concentrations of ATP. Inhibitors of vascular endothelial growth factor receptor (VEGFR) kinase against cancer angiogenesis show the advantage of some relaxation in specificity. Sorafenib, originally developed as RAF inhibitor, is now in clinical use as a VEGFR inhibitor. Temsirolimus (a derivative of rapamycin) is the only example of a drug in clinical use that does not target the kinase ATP site. Instead rapamycin, when in complex with the protein FKBP12, effectively targets mTOR kinase at a site located on a domain, the FRB domain, that appears to be involved in localisation or substrate docking.
Investigation of an outbreak of Salmonella enterica serovar Newport infection
Authors: IRVINE W. N. , GILLESPIE I. A. , SMYTH F. B. , ROONEY P. J. , McCLENAGHAN A. , DEVINE M. J. , TOHANI V. K. 
Published: March 2009

SUMMARYA large outbreak of Salmonella enterica serotype Newport infection occurred in Northern Ireland during September and October 2004. Typing of isolates from patients confirmed that this strain was indistinguishable from that in concurrent outbreaks in regions of England, in Scotland and in the Isle of Man. A total of 130 cases were distributed unequally across local government district areas in Northern Ireland. The epidemic curve suggested a continued exposure over about 4 weeks. A matched case-control study of 23 cases and 39 controls found a statistically significant association with a history of having eaten lettuce in a meal outside the home and being a case (odds ratio 23·7, 95% confidence interval 1·4–404·3). This exposure was reported by 57% of cases. Although over 300 food samples were tested, none yielded any Salmonella spp. Complexity and limited traceability in salad vegetable distribution hindered further investigation of the ultimate source of the outbreak.
Time resolved star formation in the SMC: the youngest star clusters
Authors: Sabbi Elena , Smith Linda J. , Carlson Lynn R. , Nota Antonella , Tosi Monica , Cignoni Michele , Gallagher Jay S. , Sirianni Marco , Meixner Margaret 
Published: March 2009

AbstractThe two young clusters NGC 346 and NGC 602 in the Small Magellanic Cloud provide us with the opportunity to study and the efficiency of feedback mechanism at low metallicity, as well as the impact of local and global conditions in cluster formation and evolution. I describe the latest results from a multi-wavelength, large-scale study of these two clusters. HST/ACS images reveal that the clusters have very different structures: NGC 346 is composed by a number of sub-clusters which appear coeval with ages of 3 ± 1 Myr, strongly suggesting formation by the hierarchical fragmentation of a turbulent molecular cloud (Nota et al. 2006; Sabbi et al. 2007a). NGC 602, on the contrary, appears as a single small cluster of OB stars surrounded by pre-main sequence stars. For both clusters high-resolution spectroscopy of the ionized gas shows little evidence for gas motions. This suggests that at the low SMC metallicity, the winds from the hottest stars are not powerful enough to sweep away the residual gas. Instead we find that stellar radiation is the dominant process shaping the interstellar environment of NGC 346 and NGC 602.
An observational study of GMCs in the Magellanic Clouds with the ASTE telescope
Authors: Minamidani Tetsuhiro , Mizuno Norikazu , Mizuno Yoji , Kawamura Akiko , Onishi Toshikazu , Tatematsu Ken'ichi , Hasegawa Tetsuo , Ikeda Masafumi , Fukui Yasuo 
Published: March 2009

AbstractWe report the results of the submillimeter observations with the ASTE 10 m telescope toward the giant molecular clouds (GMCs) in the Magellanic Clouds to reveal the physical properties of dense molecular gas, the principle sites of star and cluster formation. Six GMCs in the Large Magellanic Cloud have been mapped in the 12CO(J = 3 − 2) transition and 32 clumps are identified in these GMCs at a resolution of 5 pc. These data are combined with 12CO(J = 1 − 0) and 13CO(J = 1 − 0) results and compared with LVG calculations to derive the density and temperature of clumps. The derived density and temperature are distributed in wide ranges. We have made small mapping observations in the 13CO(J = 3 − 2) transition toward 9 representative peak positions of clumps to determine the density and temperature of clumps. These physical properties are constrained well and there are differences in density and temperature among clumps. We suggest that these differences of clump properties represent an evolutionary sequence of GMCs in terms of density increase leading to star formation.
Star cluster evolution in the Magellanic Clouds revisited
Authors: de Grijs Richard , Goodwin Simon P. 
Published: March 2009

AbstractThe evolution of star clusters in the Magellanic Clouds has been the subject of significant recent controversy, particularly regarding the importance and length of the earliest, largely mass-independent disruption phase (referred to as “infant mortality”). Here, we take a fresh approach to the problem, using a large, independent, and homogeneous data set of UBVR imaging observations, from which we obtain the cluster age and mass distributions in both the Large and Small Magellanic Clouds (LMC, SMC) in a self-consistent manner. We conclude that the (optically selected) SMC star cluster population has undergone at most ~30% (1σ) infant mortality between the age range from about 3–10 Myr, to that of approximately 40–160 Myr. We rule out a 90% cluster mortality rate per decade of age (for the full age range up to 109 yr) at a > 6σ level. Using a simple approach, we derive a “characteristic” cluster disruption time-scale for the cluster population in the LMC that implies that we are observing the initial cluster mass function (CMF). Preliminary results suggest that the LMC cluster population may be affected by <10% infant mortality.
Properties of X-ray binaries in the Magellanic Clouds from RXTE and Chandra observations
Authors: Corbet R. H. D. , Coe M. J. , McGowan K. E. , Schurch M. P. E. , Townsend L. J. , Galache J. L. , Marshall F. E. 
Published: March 2009

AbstractThe X-ray binary population of the SMC is very different from that of the Milky Way consisting, with one exception, entirely of transient pulsating Be/neutron star binaries. We have now been monitoring these SMC X-ray pulsars for over 10 years using the Rossi X-ray Timing Explorer with observations typically every week. The RXTE observations have been complemented with surveys made using the Chandra observatory. The RXTE observations are non-imaging but enable detailed studies of pulsing sources. In contrast, Chandra observations can provide precise source locations and detections of sources at lower flux levels, but do not provide the same timing information or the extended duration light curves that RXTE observations do. We summarize the results of these monitoring programs which provide insights into both the differences between the SMC and the Milky Way, and the details of the accretion processes in X-ray pulsars.
Optical properties of High-Mass X-ray Binaries (HMXBs) in the Small Magellanic Cloud
Authors: Coe M. J. , Corbet R. H. D. , McGowan K. E. , McBride V. A. , Schurch M. P. E. , Townsend L. J. , Galache J. L. , Negueruela I. , Buckley D. 
Published: March 2009

AbstractThe SMC represents an exciting opportunity to observe the direct results of tidal interactions on star birth. One of the best indicators of recent star birth activity is the presence of significant numbers of High-Mass X-ray Binaries (HMXBs) — and the SMC has them in abundance! We present results from nearly 10 years of monitoring these systems plus a wealth of other ground-based optical data. Together they permit us to build a picture of a galaxy with a mass of only a few percent of the Milky Way but with a more extensive HMXB population. However, as often happens, new discoveries lead to some challenging puzzles — where are the other X-ray binaries (e.g., black hole systems) in the SMC? And why do virtually all the SMC HMXBs have Be star companions? The evidence arising from these extensive optical observations for this apparently unusual stellar evolution are discussed.
Scaling Laws for Branching Vessels of Human Cerebral Cortex
Authors: FRANCIS CASSOT , FREDERIC LAUWERS , SYLVIE LORTHOIS , PRASANNA PUWANARAJAH , HENRI DUVERNOY 
Published: March 2009

ABSTRACTObjective: Vascular architecture, particularly of cerebral microvessels, has profound implications for both health and disease in a variety of areas, such as neuroimaging, angiogenesis and development, Alzheimer's disease, and vascular tumors. We analyzed the architecture of tree‐like vessels of the human cerebral cortex.Methods: Digital three‐dimensional images of the microvascular network were obtained from thick sections of India ink–injected human brain by confocal laser microscopy covering a large zone of secondary cortex. A novel segmentation method was used to extract the skeleton and measure the diameter at every vertex.Results: In this paper, we focus on the topology of the cortical tree‐like vessels. Using stem‐crown decomposition, power‐scaling laws were shown to govern the relationships between integrated parameters, such as the distal cumulative length, volume, or normalized flow. This led us toward an experimental confirmation of the allometric equation between mass and metabolic rate. Inversely, the power‐law model did not match the relationships between local parameters, such as diameter, and integrated ones. As a consequence, Murray's law did not appropriately model the architecture of cerebrovascular bifurcations.Conclusions: This study provides a unique, large database and mathematical characterization that may prove valuable for modeling the cerebral.
Statistical detection of cooperative transcription factors with similarity adjustment
Authors: Pape Utz J. , Klein Holger , Vingron Martin 
Published: March 2009

AbstractMotivation: Statistical assessment of cis-regulatory modules (CRMs) is a crucial task in computational biology. Usually, one concludes from exceptional co-occurrences of DNA motifs that the corresponding transcription factors (TFs) are cooperative. However, similar DNA motifs tend to co-occur in random sequences due to high probability of overlapping occurrences. Therefore, it is important to consider similarity of DNA motifs in the statistical assessment.Results: Based on previous work, we propose to adjust the window size for co-occurrence detection. Using the derived approximation, one obtains different window sizes for different sets of DNA motifs depending on their similarities. This ensures that the probability of co-occurrences in random sequences are equal. Applying the approach to selected similar and dissimilar DNA motifs from human TFs shows the necessity of adjustment and confirms the accuracy of the approximation by comparison to simulated data. Furthermore, it becomes clear that approaches ignoring similarities strongly underestimate P-values for cooperativity of TFs with similar DNA motifs. In addition, the approach is extended to deal with overlapping windows. We derive Chen–Stein error bounds for the approximation. Comparing the error bounds for similar and dissimilar DNA motifs shows that the approximation for similar DNA motifs yields large bounds. Hence, one has to be careful using overlapping windows. Based on the error bounds, one can precompute the approximation errors and select an appropriate overlap scheme before running the analysis.Availability: Software to perform the calculation for pairs of position frequency matrices (PFMs) is available at http://mosta.molgen.mpg.de as well as C++ source code for downloading.Contact: utz.pape@molgen.mpg.de
The Arabidopsis Callose Synthase Gene GSL8 Is Required for Cytokinesis and Cell Patterning
Authors: Chen Xiong-Yan , Liu Lin , Lee EunKyoung , Han Xiao , Rim Yeonggil , Chu Hyosub , Kim Seon-Won , Sack Fred , Kim Jae-Yean 
Published: March 2009

Abstract
Cytokinesis is the division of the cytoplasm and its separation into two daughter cells. Cell plate growth and cytokinesis appear to require callose, but direct functional evidence is still lacking. To determine the role of callose and its synthesis during cytokinesis, we identified and characterized mutants in many members of the GLUCAN SYNTHASE-LIKE (GSL; or CALLOSE SYNTHASE) gene family in Arabidopsis (Arabidopsis thaliana). Most gsl mutants (gsl1–gsl7, gsl9, gsl11, and gsl12) exhibited roughly normal seedling growth and development. However, mutations in GSL8, which were previously reported to be gametophytic lethal, were found to produce seedlings with pleiotropic defects during embryogenesis and early vegetative growth. We found cell wall stubs, two nuclei in one cell, and other defects in cell division in homozygous gsl8 insertional alleles. In addition, gsl8 mutants and inducible RNA interference lines of GSL8 showed reduced callose deposition at cell plates and/or new cell walls. Together, these data show that the GSL8 gene encodes a putative callose synthase required for cytokinesis and seedling maturation. In addition, gsl8 mutants disrupt cellular and tissue-level patterning, as shown by the presence of clusters of stomata in direct contact and by islands of excessive cell proliferation in the developing epidermis. Thus, GSL8 is required for patterning as well as cytokinesis during Arabidopsis development.
HISTONE MONOUBIQUITINATION1 Interacts with a Subunit of the Mediator Complex and Regulates Defense against Necrotrophic Fungal Pathogens inArabidopsis
Authors: Dhawan Rahul , Luo Hongli , Foerster Andrea Maria , AbuQamar Synan , Du Hai-Ning , Briggs Scott D. , Scheid Ortrun Mittelsten , Mengiste Tesfaye 
Published: March 2009

AbstractThis work examines the role of the Arabidopsis thaliana RING E3 ligase, HISTONE MONOUBIQUITINATION1 (HUB1) in disease resistance. Loss-of-function alleles of HUB1 show increased susceptibility to the necrotrophic fungal pathogens Botrytis cinerea and Alternaria brassicicola, whereas HUB1 overexpression conferred resistance to B. cinerea. By contrast, responses to the bacterial pathogen Pseudomonas syringae are unaltered in hub1 plants. hub1 mutants have thinner cell walls but increased callose around an infection site. HUB1 acts independently of jasmonate, but ethylene (ET) responses and salicylate modulate the resistance of hub1 mutants to necrotrophic fungi. The ET response factor ETHYLENE INSENSITIVE2 is epistatic to HUB1 for A. brassicicola resistance but additive to HUB1 for B. cinerea resistance. HUB1 interacts with MED21, a subunit of the Arabidopsis Mediator, a conserved complex that regulates RNA polymerase II. RNA interference lines with reduced MED21 expression are highly susceptible to A. brassicicola and B. cinerea, whereas T-DNA insertion alleles are embryonic lethal, suggesting an essential role for MED21. However, HUB1-mediated histone H2B modification is independent of histone H3 and DNA methylation. In sum, histone H2B monoubiquitination is an important chromatin modification with regulatory roles in plant defense against necrotrophic fungi most likely through modulation of gene expression.
A Chloroplastic UDP-Glucose Pyrophosphorylase fromArabidopsisIs the Committed Enzyme for the First Step of Sulfolipid Biosynthesis
Authors: Okazaki Yozo , Shimojima Mie , Sawada Yuji , Toyooka Kiminori , Narisawa Tomoko , Mochida Keiichi , Tanaka Hironori , Matsuda Fumio , Hirai Akiko , Hirai Masami Yokota , Ohta Hiroyuki , Saito Kazuki 
Published: March 2009

AbstractPlants synthesize a sulfur-containing lipid, sulfoquinovosyldiacylglycerol, which is one of three nonphosphorus glycerolipids that provide the bulk of the structural lipids in photosynthetic membranes. Here, the identification of a novel gene, UDP-glucose pyrophosphorylase3 (UGP3), required for sulfolipid biosynthesis is described. Transcriptome coexpression analysis demonstrated highly correlated expression of UGP3 with known genes for sulfolipid biosynthesis in Arabidopsis thaliana. Liquid chromatography–mass spectrometry analysis of leaf lipids in two Arabidopsis ugp3 mutants revealed that no sulfolipid was accumulated in these mutants, indicating the participation of UGP3 in sulfolipid biosynthesis. From the deduced amino acid sequence, UGP3 was presumed to be a UDP-glucose pyrophosphorylase (UGPase) involved in the generation of UDP-glucose, serving as the precursor of the polar head of sulfolipid. Recombinant UGP3 was able to catalyze the formation of UDP-glucose from glucose-1-phosphate and UTP. A transient assay using fluorescence fusion proteins and UGPase activity in isolated chloroplasts indicated chloroplastic localization of UGP3. The transcription level of UGP3 was increased by phosphate starvation. A comparative genomics study on UGP3 homologs across different plant species suggested the structural and functional conservation of the proteins and, thus, a committing role for UGP3 in sulfolipid synthesis.
Obligate Heterodimerization ofArabidopsisPhytochromes C and E and Interaction with the PIF3 Basic Helix-Loop-Helix Transcription Factor
Authors: Clack Ted , Shokry Ahmed , Moffet Matt , Liu Peng , Faul Michael , Sharrock Robert A. 
Published: March 2009

AbstractPhytochromes are dimeric chromoproteins that regulate plant responses to red (R) and far-red (FR) light. The Arabidopsis thaliana genome encodes five phytochrome apoproteins: type I phyA mediates responses to FR, and type II phyB–phyE mediate shade avoidance and classical R/FR-reversible responses. In this study, we describe the complete in vivo complement of homodimeric and heterodimeric type II phytochromes. Unexpectedly, phyC and phyE do not homodimerize and are present in seedlings only as heterodimers with phyB and phyD. Roles in light regulation of hypocotyl length, leaf area, and flowering time are demonstrated for heterodimeric phytochromes containing phyC or phyE. Heterodimers of phyC and chromophoreless phyB are inactive, indicating that phyC subunits require spectrally intact dimer partners to be active themselves. Consistent with the obligate heterodimerization of phyC and phyE, phyC is made unstable by removal of its phyB binding partner, and overexpression of phyE results in accumulation of phyE monomers. Following a pulse of red light, phyA, phyB, phyC, and phyD interact in vivo with the PHYTOCHROME INTERACTING FACTOR3 basic helix-loop-helix transcription factor, and this interaction is FR reversible. Therefore, most or all of the type I and type II phytochromes, including heterodimeric forms, appear to function through PIF-mediated pathways. These findings link an unanticipated diversity of plant R/FR photoreceptor structures to established phytochrome signaling mechanisms.
Investigation of film cooling effectiveness and heat transfer coefficient for rectangular holes with two rows
Authors: Koç İbrahim , İslamoğlu Yaşar , Akdağ Ünal 
Published: March 2009

PurposeThe purpose of this paper is to investigate the film cooling effectiveness and heat transfer coefficient in a flat plate with two rows of rectangular injection holes.Design/methodology/approachExperimental and numerical investigation of film cooling effectiveness in a flat plate with two rows which are rectangular injection holes. The liquid crystal technique has been used for measuring the heat transfer coefficients on the mixture region. Three injection holes in model are in a single row. The holes are rectangular cross section and they are 9 × 6.5 mm. The injection holes are inclined at 30° along the mainstream direction. The blowing ratios are from 0.5 to 2.0. The experiments and their computational models are established to investigate its effects at the 330 and 340 and 350 K injection temperatures and the different blowing ratios.FindingsThe results show that the film cooling effectiveness and heat transfer coefficient of a given flat plate surface, both along the mainstream and lateral direction, depend on the optimum selection of parameters. In this study, the highest effectiveness is determined at a blowing ratio of 0.5. Further increasing the ratio results in reverse effect on the film cooling effectiveness.Originality/valueIt is the fist time the film cooling effectiveness is compared at the rectangular injection holes with two rows as experimental and numerical.
Studies of zenith pass tracing of the inter‐satellite linkage antenna based on mechanical tilting
Authors: kun Zhai , Di Yang 
Published: March 2009

PurposeThe purpose of this paper is to provide a feasible method to solve the zenith pass problem that can occur when the inter‐satellite linkage antenna of the user satellite is tracing TDRS. The antenna uses the elevation‐over‐azimuth architecture.Design/methodology/approachThe movement laws of the inter‐satellite linkage can be obtained based on the orbit predictions of the user satellite and TDRS. According to the movement laws, the zenith pass moments and blindness zones are found. The trajectory preprocessor is provided to design a command trajectory for driving the axis of the tilting mechanism.FindingsIn the worst situation, the blindness zone can appear once every half day. Three special orbit altitude values are obtained. When the user satellite picks one of them as its orbit altitude, the blindness zone may be avoided forever. The zenith pass tracing strategies based on the mechanical tilting method have been designed.Research limitations/implicationsThis method obtains the stable tracking during the zenith pass course by changing the hardware structure of the antenna. It is too expensive and can influence the pointing precision of the antenna.Practical implicationsThe research can help the engineers analyze and solve the zenith pass problem of the antenna.Originality/valueThis paper studies the zenith pass problem that can occur when the inter‐satellite linkage antenna of the user satellite is tracing TDRS and provides a solving method.