bluuebunny/crossref_metadata_2025_split huggingface dataset:
Selectivity of Neutral/Weakly Basic P1 Group Inhibitors of Thrombin and Trypsin by a Molecular Dynamics Study
Authors: Wu Emilia L. , Han KeLi , Zhang John Z. H. 
Published: August 2008

AbstractMolecular dynamics (MD) simulations followed by molecular mechanics generalized Born surface area (MM‐GBSA) analyses have been carried out to study the selectivity of two neutral and weakly basic P1 group inhibitors (177 and CDA) to thrombin and trypsin. Detailed binding free energies between these inhibitors and individual protein residues are calculated by using a per‐residue basis decomposition method. The analysis of the detailed interaction energies provides insight on the protein–inhibitor‐binding mechanism and helps to elucidate the basis for achieving selectivity through interpretation of the structural and energetic results from the simulations. The study shows that the dominant factor of selectivity for both inhibitors is van der Waals energy, which suggests better shape complementarity and packing with thrombin. Nonpolar solvation free energy and total entropy contribution are also in favor of selectivity, but the contributions are much smaller. Binding mode and structural analysis show that 177 binds to thrombin and trypsin in a similar binding mode. In contrast, the CDA binds to thrombin and trypsin in very different modes.
Metallobiological Necklaces: Mass Spectrometric and Molecular Modeling Study of Metallation in Concatenated Domains of Metallothionein
Authors: Chan Jayna , Huang Zuyun , Watt Ian , Kille Peter , Stillman Martin 
Published: August 2008

AbstractThe ubiquitous protein metallothionein (MT) has proven to be a major player not only in the homeostasis of CuI and ZnII, but also binds all the Group 11 and 12 metals. Metallothioneins are characterised by the presence of numerous cys‐x‐cys and cys–cys motifs in the sequence and are found naturally with either one domain or two, linked, metal‐binding domains. The use of chains of these metal–thiolate domains offers the possibility of creating chemically tuneable and, therefore, chemically dependent electrochemical or photochemical surface modifiers or as nanomachinery with nanomechanical properties. In this work, the metal‐binding properties of the Cd4‐containing domain of α‐rhMT1a assembled into chains of two and three concatenated domains, that is, “necklaces”, have been studied by spectrometric techniques, and the interactions within the structures modelled and interpreted by using molecular dynamics. These chains are metallated with 4, 8 or 12 CdII ions to the 11, 22, and 33 cysteinyl sulfur atoms in the α‐rhMT1a, αα‐rhMT1a, and ααα‐rhMT1a proteins, respectively. The effect of pH on the folding of each protein was studied by ESI‐MS and optical spectroscopy. MM3/MD simulations were carried out over a period of up to 500 ps by using force‐field parameters based on the reported structural data. These calculations provide novel information about the motion of the clustered metallated, partially demetallated, and metal‐free peptide chains, with special interest in the region of the metal‐binding site. The MD energy/time trajectory conformations show for the first time the flexibility of the metal–sulfur clusters and the bound amino acid chains. We report unexpected and very different sizes for the metallated and demetallated proteins from the combination of experimental data, with molecular dynamics simulations.
Controllable Cyclization Reactions of 2‐(2′,3′‐Allenyl)acetylacetates Catalyzed by Gold and Palladium Affording Substituted Cyclopentene and 4,5‐Dihydrofuran Derivatives with Distinct Selectivity
Authors: Jiang Xuefeng , Ma Xiaojing , Zheng Zilong , Ma Shengming 
Published: August 2008

AbstractEfficient room‐temperature syntheses of cyclopentenes and 4,5‐dihydrofurans with different substitution patterns were performed starting from the same materials (i.e., 2‐(2′,3′‐allenyl)acetylacetates). Depending on the choice of metal catalyst, the Au‐catalyzed reaction afforded C‐attack‐5‐endo cyclization products 2, whereas the Pd‐catalyzed one led to the formation of O‐attack‐5‐exo cyclization products 3. The selectivity may be explained by the steric and electronic effects of the substrates and catalysts.
Bonding and Bending in Zirconium(IV) and Hafnium(IV) Hydrazides
Authors: Herrmann Heike , Fillol Julio Lloret , Gehrmann Thorsten , Enders Markus , Wadepohl Hubert , Gade Lutz H. 
Published: August 2008

AbstractReaction of the dichloro complexes [M(N2TBSNpy)Cl2] (M=Zr: 1, Hf: 2; TBS: tBuMe2Si; py: pyridine) with one molar equivalent of LiNHNPh2 gave mixtures of the two diastereomeric chlorohydrazido(1−) complexes [M(N2TBSNpy)(NHNPh2)Cl] (M=Zr: 3 a,b, Hf: 4 a,b) in which the diphenylhydrazido(1−) ligand adopts a bent κ1 coordination. This mixture of isomers could be cleanly converted into the deep green diphenylhydrazido(2−) complexes [Zr(N2TBSNpy)(NNPh2)(py)] (5) and [Hf(N2TBSNpy)(NNPh2)(py)] (6), respectively, by dehydrohalogenation with lithium hexamethyldisilazide (LiHMDS) in the presence of one molar equivalent of pyridine. Both complexes contain a linearly coordinated hydrazinediide for which a DFT‐based frontier orbital analysis established bonding through one σ and two π orbitals. A high polarity of the MN bond was found, in accordance with the description of hydrazinediide(2−) acting as a six‐electron donor ligand. The pyridine ligand in [M(N2TBSNpy)(NNPh2)(py)] (M=Zr: 5, Hf: 6) is substitutionally labile as established by line‐shape analysis of the dynamic spectra (ΔG≠=19 kcal mol−1). A change in denticity of the hydrazido unit from κ1 to κ2 was studied by DFT methods. Both forms are calculated to be very close in energy and are only separated by shallow activation barriers, which supports the notion of a rapid κ1 to κ2 interconversion. This process is believed to happen early on in the NN scission in the presence of coupling reagents. Frontier orbital and natural population analyses suggest that a primarily charge‐controlled nucleophilic attack at Nα is unlikely whereas interaction with an electrophile could play an important role. This hypothesis was tested by the reaction of 5 and 6 with one molar equivalent of B(C6F5)3 to give [Zr(N2TBSNpy)(NNPh2){B(C6F5)3}] (7) and [Hf(N2TBSNpy)(NNPh2){B(C6F5)3}] (8). In these products, B(C6F5)3 becomes attached to the Nα atom of the side‐on bound hydrazinediide and there is an additional interaction of an ortho‐F atom of a C6F5 ring with the metal centre.
Synthesis and Preferred All‐syn Conformation of C3‐Symmetrical N‐(Hetero)arylmethyl Triindoles
Authors: García‐Frutos Eva M. , Gómez‐Lor Berta , Monge Ángeles , Gutiérrez‐Puebla Enrique , Alkorta Ibon , Elguero José 
Published: August 2008

AbstractA new series of C3‐symmetrical N‐(hetero)arylmethyl triindoles has been synthesized in a straightforward procedure. The structure and conformation in the solid state have been determined for three derivatives (3, 4, and 6) by X‐ray crystallographic analysis. In all three cases, the molecules adopt a tripodal conformation with all of the flexible arms directed towards the same side, thereby delimiting an inner cavity. Compound 6 crystallizes and forms C3‐symmetric dimeric cagelike complexes. Guest molecules of chloroform and water are confined within the resulting cavities with stabilization by different intermolecular interactions; this highlights the potential of these compounds in the construction of supramolecular systems. A computational analysis has been performed to predict the most stable conformers. As a general trend, a preference for a conformation with all branches directed to the same side has been predicted. Comparison between theoretical and experimental results indicates that the computational level selected for the present study, B3LYP/6‐31G*, is able to reproduce both the minimum energy conformations and the rotation barriers about the NCH2 bond.
Cell adhesion in zebrafish myogenesis: Distribution of intermediate filaments, microfilaments, intracellular adhesion structures and extracellular matrix
Authors: Costa Manoel L. , Escaleira Roberta C. , Jazenko Fernanda , Mermelstein Claudia S. 
Published: August 2008

AbstractTo overcome the limitations of in vitro studies, we have been studying myogenesis in situ in zebrafish embryos, at a sub‐cellular level. While in previous works we focused on myofibrillogenesis and some aspects of adhesion structures, here we describe in more detail cell adhesion structures and interactions among cytoskeletal components, membrane and extracellular matrix during zebrafish muscle development. We studied the intermediate filaments, and we describe the full range of desmin distribution in zebrafish development, from perinuclear to striated, until its deposition around the intersomite septa of older somites. This adhesion structure, positive for desmin and actin, has not been previously observed in myogenesis in vitro. We also show that actin is initially located in the intersomite septum region whereas it is confined to the myofibrils later on. While actin localization changes during development, the adhesion complex proteins vinculin, paxillin, talin, dystrophin, laminin and fibronectin always appear exclusively at the intersomite septa, and appear to be co‐distributed, even though the extracellular proteins accumulates before the intracellular ones. Contrary to the adhesion proteins, that are continuously distributed, desmin and sarcomeric actin form triangular aggregates among the septa and the cytoskeleton. We studied the cytoskeletal linker plectin as well, and we show that it has a distribution similar to desmin and not to actin. We conclude that the in situ adhesion structures differ from their in vitro counterparts, and that the actual zebrafish embryo myogenesis is quite different than that which occurs in in vitro systems. Cell Motil. Cytoskeleton 65: 801–815, 2008. © 2008 Wiley‐Liss, Inc.
Long‐term outcomes of radical prostatectomy with multimodal adjuvant therapy in men with a preoperative serum prostate‐specific antigen level ≥50 ng/mL
Authors: Inman Brant A. , Davies Judson D. , Rangel Laureano J. , Bergstralh Eric J. , Kwon Eugene D. , Blute Michael L. , Karnes R. Jeffrey , Leibovich Bradley C. 
Published: August 2008

AbstractBACKGROUND.The authors evaluated the long‐term outcomes of men with prostate cancer and very high (≥50 ng/mL) preoperative serum prostate‐specific antigen (PSA) values that were treated with radical prostatectomy.METHODS.This study included 236 men with preoperative serum PSA values ≥50ng/mL who underwent radical retropubic prostatectomy between 1987 and 2004. For comparison, the study cohort was divided into 2 groups: patients with PSA levels between 50 and 99 ng/mL and patients with PSA levels ≥100 ng/mL. Biochemical recurrence was defined as a single postoperative serum PSA value of 0.4 ng/mL or greater. Systemic disease progression was defined as the development of a local recurrence or systemic metastases, and any death resulting from prostate cancer or its treatment was defined as a cancer‐specific mortality.RESULTS.Biochemical recurrence‐free survival rates in the groups of patients with a PSA level 50 to 99 ng/mL and ≥100 ng/mL were 43% and 36% at 10 years, respectively. Systemic progression‐free survival rates in the PSA 50 to 99 ng/mL and PSA ≥100 ng/mL groups were 83% and 74% at 10 years, respectively. Estimated overall cancer‐specific survival was 87% at 10 years.CONCLUSIONS.Patients with prostate cancer and a serum PSA level ≥50 ng/mL have very high‐risk prostate cancer that carries a high likelihood of being pathologically advanced. Although the probability of realizing long‐term survival in these high‐risk patients is less than in patients with more favorable disease, 10‐year survival outcomes remain excellent and argue for aggressive management of these cases. Cancer 2008. © 2008 American Cancer Society.
Differential expression of the multidrug resistance‐related proteins ABCb1 and ABCc1 between blood‐brain interfaces
Authors: Gazzin Silvia , Strazielle Nathalie , Schmitt Charlotte , Fevre‐Montange Michelle , Ostrow J. Donald , Tiribelli Claudio , Ghersi‐Egea Jean‐François 
Published: August 2008

AbstractCerebral homeostasis results from the presence of the protective blood‐brain and blood‐cerebrospinal fluid barriers located respectively at the brain capillary endothelium and the choroid plexus epithelium. ABCb1 (Pgp) and ABCc1 (Mrp1) transporters are two major proteins of neuroprotection whose localization and functional significance at both barriers remain partly unsettled. We conducted a comparative analysis of their relative protein content between the two blood‐brain interfaces. Microvessels and choroid plexuses located in the fourth and lateral ventricles were isolated from developing and adult rat brains, and whole homogenates were submitted to quantitative Western blot analysis by using standard curves generated from one of the samples. In adult, choroid plexus‐associated Pgp content was less than 0.5% of the level in microvessels, whereas Mrp1 content in microvessels was 4% of that in the fourth ventricle choroid plexus. Pgp but not Mrp1 was enriched in microvessels over parenchyma. In choroid plexuses, Mrp1 displayed a basolateral epithelial localization, and reached its high adult protein level, early during postnatal development. In postnatal as in adult microvessels, Pgp localization appeared luminal. However, by contrast to Mrp1, the level of this transporter increased 4.6‐fold between 9‐day‐old and adult animals. Western blot analysis of human samples confirmed the mirror image of Pgp and Mrp1 expression between the two barriers. We conclude that there are major differences in the mechanisms by which blood‐brain interfaces fulfill their neuroprotective functions. The data also highlight the significance of the neuroprotective function of the choroid plexus during brain maturation, when the microvasculature is still developing. J. Comp. Neurol. 510:497–507, 2008. © 2008 Wiley‐Liss, Inc.
Dual‐Polarization Imaging of a Dual‐Fluorophore Ion Sensor: A Single‐Molecule Study
Authors: Lu Yin , Bowles Richard K. , Paige Matthew F. 
Published: August 2008

AbstractThe fluorescence emission of the dual‐fluorophore Ca2+ ion sensor molecule, calcium‐green 2 (CG‐2), has been characterized using dual‐polarization imaging at the single‐molecule level. By comparing the fluorescence intensity of individual CG‐2 molecules in two mutually orthogonal polarization image channels, information about the relative orientation of the two constituent fluorophores in the molecule is obtained. Experimental results from polarization measurements are compared with those predicted from a geometric model based on coupled‐fluorophores that are randomly distributed in space. The results confirm previous optical spectroscopy‐based predictions of the orientation of CG‐2′s fluorophores, and the general applications of this dual‐polarization imaging approach for characterizing the optical properties of molecules containing multiple fluorophores is discussed.
Analog circuit design by nonconvex polynomial optimization: Two design examples
Authors: Lui Siu‐Hong , Kwan Hing‐Kit , Wong Ngai 
Published: August 2008

AbstractWe present a framework for synthesizing low‐power analog circuits through global optimization over generally nonconvex multivariate polynomial objective function and constraints. Specifically, a nonconvex optimization problem is formed, which is then efficiently solved through convex programming techniques based on linear matrix inequality (LMI) relaxation. The framework allows both polynomial inequality and equality constraints, thereby facilitating more accurate device modelings and parameter tuning. Compared to traditional nonlinear programming (NLP), the proposed methodology exhibits superior computational efficiency, and guarantees convergence to a globally optimal solution. As in other physical design tasks, circuit knowledge and insight are critical for initial problem formulation, while the nonconvex optimization machinery provides a versatile tool and systematic way to locate the optimal parameters meeting design specifications. Two circuit design examples are given, namely, a nested transconductance(Gm)–capacitance compensation (NGCC) amplifier and a delta–sigma (ΔΣ) analog‐to‐digital converter (ADC), both of them being the key components in many electronic systems. Copyright © 2008 John Wiley & Sons, Ltd.
The geochemistry of the volcanic rocks of Canouan, Grenadine islands, Lesser Antilles arc
Authors: Smith T. E. , Holm P. E. , Thirlwall M. F. 
Published: August 2008

AbstractIn late Oligocene or early Miocene, a series of basalts and basaltic andesites erupted on the island of Canouan and formed the Old Volcanic Massif (OVM). In a second eruptive phase a series of basalts, basaltic andesites and andesites formed the upper part of the Canouan Formation (CF; lower Middle Miocene; post‐16 Ma) and the Upper Volcanic System (UVS; end‐Miocene; 6.8 Ma). These two eruptive phases are characterized by systematic differences in isotope ratios and chemical composition. The OVM rocks have 87Sr/86Sr and 143Nd/144Nd ratios ranging from 0.70512 to 0.70657 and 0.512415 to 0.512414, whereas in the CF/UVS rocks the ratios range from 0.70454 to 0.70493 and 0.512924 to 0.512843. In addition, the rocks of OVM also have lower ΣFe2O3 and Co contents, and higher La/Yb ratios than those of the CF/UVS. The isotopic and chemical data suggest that both suites were formed from similar partial melts of a subduction‐modified, depleted spinel‐lherzolite source. These data also show that the OVM melts assimilated relatively large amounts of highly radiogenic crustal material, whereas the CF/UVS melts assimilated relatively small amounts of highly radiogenic crustal material. The chemical and isotopic variations of the OVM rocks are consistent with the removal of mixtures of clinopyroxene, plagioclase and magnetite during assimilation‐fractional‐crystallization. Within the CF/UVS, the chemical and isotopic variations can be explained in terms of minor crustal assimilation; the removal of olivine, clinopyroxene, plagioclase and magnetite to form the basalts and basaltic andesites; and the removal of clinopyroxene, plagioclase, magnetite and amphibole to form the andesites. Copyright © 2008 John Wiley & Sons, Ltd.
Phosphatase and tensin homolog (PTEN) regulates hepatic lipogenesis, microsomal triglyceride transfer protein, and the secretion of apolipoprotein B–containing lipoproteins
Authors: Qiu Wei , Federico Lisa , Naples Mark , Avramoglu Rita Kohen , Meshkani Reza , Zhang Jing , Tsai Julie , Hussain Mahmood , Dai Kezhi , Iqbal Jahangir , Kontos Christopher D. , Horie Yasuo , Suzuki Akira , Adeli Khosrow 
Published: August 2008

Abstract

Hepatic apolipoprotein B (apoB) lipoprotein production is metabolically regulated

via

the phosphoinositide 3-kinase cascade; however, the role of the key negative regulator of this pathway, the tumor suppressor phosphatase with tensin homology (PTEN), is unknown. Here, we demonstrate that hepatic protein levels of apoB100 and microsomal triglyceride transfer protein (MTP) are significantly down-regulated (73% and 36%, respectively) in the liver of PTEN liver-specific knockout (KO) mice, and this is accompanied by increased triglyceride (TG) accumulation and lipogenic gene expression, and reduced hepatic apoB secretion in freshly isolated hepatocytes. MTP protein mass and lipid transfer activity were also significantly reduced in liver of PTEN KO mice. Overexpression of the dominant negative mutant PTEN C/S124 (adenovirus expressing PTEN C/S mutant [AdPTENC/S]) possessing constitutive phospoinositide 3-kinase activity in HepG2 cells led to significant reductions in both secreted apoB100 and cellular MTP mass (76% and 34%, respectively), and increased messenger RNA (mRNA) levels of sterol regulatory element binding protein 1c (SREBP-1c), fatty acid synthase (FAS), and acetyl-CoA carboxylase (ACC). Reduced apoB100 secretion induced by AdPTENC/S was associated with increased degradation of newly-synthesized cellular apoB100, in a lactacystin-sensitive manner, suggesting enhanced proteasomal degradation. AdPTENC/S also reduced apoB-lipoprotein production in McA-RH7777 and primary hamster hepatocytes. Our findings suggest a link between PTEN expression and hepatic production of apoB-containing lipoproteins. We postulate that perturbations in PTEN not only may influence hepatic insulin signaling and hepatic lipogenesis, but also may alter hepatic apoB-lipoprotein production and the MTP stability. On loss of PTEN activity, increased lipid substrate availability in the face of reduced hepatic lipoprotein production capacity can rapidly lead to hepatosteatosis and fatty liver. (Hepatology 2008;48:1799–1809.)
Single neuron binding properties and the magical number 7
Authors: Migliore Michele , Novara Gaspare , Tegolo Domenico 
Published: August 2008

AbstractWhen we observe a scene, we can almost instantly recognize a familiar object or can quickly distinguish among objects differing by apparently minor details. Individual neurons in the medial temporal lobe of humans have been shown to be crucial for the recognition process, and they are selectively activated by different views of known individuals or objects. However, how single neurons could implement such a sparse and explicit code is unknown and almost impossible to investigate experimentally. Hippocampal CA1 pyramidal neurons could be instrumental in this process. Here, in an extensive series of simulations with realistic morphologies and active properties, we demonstrate how n radial (oblique) dendrites of these neurons may be used to bind n inputs to generate an output signal. The results suggest a possible neural code as the most effective n‐ple of dendrites that can be used for short‐term memory recollection of persons, objects, or places. Our analysis predicts a straightforward physiological explanation for the observed puzzling limit of about 7 short‐term memory items that can be stored by humans. © 2008 Wiley‐Liss, Inc.
Spatial learning results in elevated agmatine levels in the rat brain
Authors: Liu Ping , Collie Nicola D. , Chary Sree , Jing Yu , Zhang Hu 
Published: August 2008

AbstractAccumulating evidence suggests that agmatine, a metabolite of L‐arginine by arginine decarboxylase, is a novel neurotransmitter, and exogenous agmatine can modulate behavior functions including learning and memory. However, direct evidence of its involvement in learning and memory processes is currently lacking. This study measured agmatine levels in the hippocampus, parahippocampal region, cerebellum, and vestibular nucleus in rats that were trained to find a hidden escape platform in the water‐maze task, or forced to swim in the pool with no platform presented, or kept in the holding‐box, using liquid chromatography/mass spectrometry. Compared with the swimming only group and holding‐box group, agmatine levels were significantly increased in the CA1 and dentate gyrus subregions of the hippocampus, the entorhinal cortex and the vestibular nucleus in the water‐maze training group. These results, for the first time, demonstrate spatial learning‐induced region‐specific elevation in agmatine, and raise a novel issue of the involvement of agmatine in the processes of learning and memory. © 2008 Wiley‐Liss, Inc.