bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neuroendocrine differentiation in the 12T‐10 transgenic prostate mouse model mimics endocrine differentiation of pancreatic beta cells
Authors: Gupta Aparna , Wang Yongqing , Browne Christopher , Kim Susan , Case Tom , Paul Manik , Wills Marcia L. , Matusik Robert J. 
Published: November 2007

AbstractBACKGROUNDNeuroendocrine (NE) prostate cancer develops as an aggressive disease that does not respond to androgen ablation therapy. It has been demonstrated that the paracrine action of NE cells facilitates the progression of androgen dependent adenocarcinoma to an androgen independent state, suggesting a significant role for NE cells during failure of androgen ablation therapy.METHODSTo investigate the pathways that are involved in NE differentiation of prostate cancer, we have looked at the expression of genes known to be involved in endocrine differentiation of β‐cells in the pancreas. This study has been performed using the NE prostate cancer mouse model (12T‐10) and the derivative allograft model (NE‐10).RESULTSImmunohistochemical studies have shown that the neuroendocrine prostate tumors express the transcription factors Foxa2, mouse achaete‐scute homolog‐1 (mash‐1), neurogenin3 (Ngn3) and Nkx2.2. These tumors show a loss of hairy/enhancer of split (Hes‐1), a gene that inhibits NE differentiation. Human NE prostate cancers also express Foxa2 and human achaete‐scute homolog‐1 (HASH‐1). These genes are expressed in NE prostate tumors in the similar sequential manner as they appear in a pancreatic β‐cell endocrine differentiation. Foxa2 expression is detected in early prostatic intraepithelial neoplasia (PIN). Mash‐1 expression is detected in a few clusters within low grade PIN lesions and Nkx2.2 expression is rarely detected in individual scattered cells within the PIN lesion. Ngn3 and Nkx2.2 frequently appear in the invasive NE cancer. Subsequent NE metastasis to lung and liver show a distinct gene expression pattern. The lung metastasis expresses Ngn3 but does not express Nkx2.2 whereas liver metastases do not express Ngn3 but express Nkx2.2.CONCLUSIONSThese results suggest that Ngn3 and Nkx2.2 expression are markers for site‐specific metastasis and/or transcriptionally regulated genes that are required for organ‐specific metastasis. This study indicates that a pathway similar to pancreatic β‐cell differentiation is involved in NE differentiation of prostate cancer. Prostate 68: 50–60, 2008. © 2007 Wiley‐Liss, Inc.
Information and discrimination in pairwise contact potentials
Authors: Solis Armando D. , Rackovsky S. 
Published: November 2007

AbstractWe examine the information‐theoretic characteristics of statistical potentials that describe pairwise long‐range contacts between amino acid residues in proteins. In our work, we seek to map out an efficient information‐based strategy to detect and optimally utilize the structural information latent in empirical data, to make contact potentials, and other statistically derived folding potentials, more effective tools in protein structure prediction. Foremost, we establish fundamental connections between basic information‐theoretic quantities (including the ubiquitous Z‐score) and contact “energies” or scores used routinely in protein structure prediction, and demonstrate that the informatic quantity that mediates fold discrimination is the total divergence. We find that pairwise contacts between residues bear a moderate amount of fold information, and if optimized, can assist in the discrimination of native conformations from large ensembles of native‐like decoys. Using an extensive battery of threading tests, we demonstrate that parameters that affect the information content of contact potentials (e.g., choice of atoms to define residue location and the cut‐off distance between pairs) have a significant influence in their performance in fold recognition. We conclude that potentials that have been optimized for mutual information and that have high number of score events per sequence–structure alignment are superior in identifying the correct fold. We derive the quantity “information product” that embodies these two critical factors. We demonstrate that the information product, which does not require explicit threading to compute, is as effective as the Z‐score, which requires expensive decoy threading to evaluate. This new objective function may be able to speed up the multidimensional parameter search for better statistical potentials. Lastly, by demonstrating the functional equivalence of quasi‐chemically approximated “energies” to fundamental informatic quantities, we make statistical potentials less dependent on theoretically tenuous biophysical formalisms and more amenable to direct bioinformatic optimization. Proteins 2008. © 2007 Wiley‐Liss, Inc.
Use of L‐asparagine and N‐phosphonacetyl‐L‐asparagine to investigate the linkage of catalysis and homotropic cooperativity in E. coli aspartate transcarbomoylase
Authors: Cardia James P. , Eldo Joby , Xia Jiarong , O'Day Elizabeth M. , Tsuruta Hiro , Gryncel Kimberly R. , Kantrowitz Evan R. 
Published: November 2007

AbstractThe mechanism of domain closure and the allosteric transition of Escherichia coli aspartate transcarbamoylase (ATCase) are investigated using L‐Asn, in the presence of carbamoyl phosphate (CP), and N‐phosphonacetyl‐L‐asparagine (PASN). ATCase was found to catalyze the carbamoylation of L‐Asn with a Km of 122 mM and a maximal velocity 10‐fold lower than observed with the natural substrate, L‐Asp. As opposed to L‐Asp, no cooperativity was observed with respect to L‐Asn. Time‐resolved small‐angle X‐ray scattering (SAXS) and fluorescence experiments revealed that the combination of CP and L‐Asn did not convert the enzyme from the T to the R state. PASN was found to be a potent inhibitor of ATCase exhibiting a KD of 8.8 μM. SAXS experiments showed that PASN was able to convert the entire population of molecules to the R state. Analysis of the crystal structure of the enzyme in the presence of PASN revealed that the binding of PASN was similar to that of the R‐state complex of ATCase with N‐phosphonaceyl‐L‐aspartate, another potent inhibitor of the enzyme. The linking of CP and L‐Asn into one molecule, PASN, correctly orients the asparagine moiety in the active site to induce domain closure and the allosteric transition. This entropic effect allows for the high affinity binding of PASN. However, the binding of L‐Asn, in the presence of a saturating concentration of CP, does not induce the closure of the two domains of the catalytic chain, nor does the enzyme undergo the transition to the high‐activity high‐ affinity R structure. These results imply that Arg229, which interacts with the β‐carboxylate of L‐Asp, plays a critical role in the orientation of L‐Asp in the active site and demonstrates the requirement of the β‐carboxylate of L‐Asp in the mechanism of domain closure and the allosteric transition in E. coli ATCase. Proteins 2008. © 2007 Wiley‐Liss, Inc.
Probing ligand binding modes of human cytochrome P450 2J2 by homology modeling, molecular dynamics simulation, and flexible molecular docking
Authors: Li Weihua , Tang Yun , Liu Hong , Cheng Jiagao , Zhu Weiliang , Jiang Hualiang 
Published: November 2007

AbstractCytochrome P450 (P450) 2J2 catalyzes epoxidation of arachidonic acid to eicosatrienoic acids, which are related to a variety of diseases such as coronary artery disease, hypertension, and carcinogenesis. Recent experimental data also suggest that P450 2J2 could be a novel biomarker and a potential target for cancer therapy. However, the active site topology and substrate specificity of this enzyme remain unclear. In this study, a three‐dimensional model of human P450 2J2 was first constructed on the basis of the crystal structure of human P450 2C9 in complex with a substrate using homology modeling method, and refined by molecular dynamics simulation. Flexible docking approaches were then employed to dock four ligands into the active site of P450 2J2 in order to probe the ligand‐binding modes. By analyzing the results, active site architecture and certain key residues responsible for substrate specificity were identified on the enzyme, which might be very helpful for understanding the enzyme's biological role and providing insights for designing novel inhibitors of P450 2J2. Proteins 2008. © 2007 Wiley‐Liss, Inc.
Using scores derived from statistical coupling analysis to distinguish correct and incorrect folds in de‐novo protein structure prediction
Authors: Bartlett Gail J. , Taylor William R. 
Published: November 2007

AbstractDistinguishing native from non‐native folds remains a challenging problem for protein structure prediction. We describe a method, SCA‐distance scoring, based on results from statistical coupling analysis which discriminates between native and non‐native folds produced by a de novo protein structure prediction method for four out of five test proteins. The method is particularly good at discriminating non‐native folds which are close in RMSD to the true fold but contain a change in an internal structural element. SCA‐distance scoring is a useful addition to the tools available for distinguishing native from non‐native folds in protein structure prediction. Proteins 2008. © 2007 Wiley‐Liss, Inc.
Analysis of the protein kinome of Entamoeba histolytica
Authors: Anamika K. , Bhattacharya A. , Srinivasan N. 
Published: November 2007

AbstractProtein kinases play important roles in almost all major signaling and regulatory pathways of eukaryotic organisms. Members in the family of protein kinases make up a substantial fraction of eukaryotic proteome. Analysis of the protein kinase repertoire (kinome) would help in the better understanding of the regulatory processes. In this article, we report the identification and analysis of the repertoire of protein kinases in the intracellular parasite Entamoeba histolytica. Using a combination of various sensitive sequence search methods and manual analysis, we have identified a set of 307 protein kinases in E. histolytica genome. We have classified these protein kinases into different subfamilies originally defined by Hanks and Hunter and studied these kinases further in the context of noncatalytic domains that are tethered to catalytic kinase domain. Compared to other eukaryotic organisms, protein kinases from E. histolytica vary in terms of their domain organization and displays features that may have a bearing in the unusual biology of this organism. Some of the parasitic kinases show high sequence similarity in the catalytic domain region with calmodulin/calcium dependent protein kinase subfamily. However, they are unlikely to act like typical calcium/calmodulin dependent kinases as they lack noncatalytic domains characteristic of such kinases in other organisms. Such kinases form the largest subfamily of kinases in E. histolytica. Interestingly, a PKA/PKG‐like subfamily member is tethered to pleckstrin homology domain. Although potential cyclins and cyclin‐dependent kinases could be identified in the genome the likely absence of other cell cycle proteins suggests unusual nature of cell cycle in E. histolytica. Some of the unusual features recognized in our analysis include the absence of MEK as a part of the Mitogen Activated Kinase signaling pathway and identification of transmembrane region containing Src kinase‐like kinases. Sequences which could not be classified into known subfamilies of protein kinases have unusual domain architectures. Many such unclassified protein kinases are tethered to domains which are Cysteine‐rich and to domains known to be involved in protein–protein interactions. Our kinome analysis of E. histolytica suggests that the organism possesses a complex protein phosphorylation network that involves many unusual kinases. Proteins 2008. © 2007 Wiley‐Liss, Inc.
Clustering orthologous proteins across phylogenetically distant species
Authors: Kim Sunshin , Kang Jaewoo , Chung Yong Je , Li Jinyan , Ryu Keun Ho 
Published: November 2007

AbstractThe quality of orthologous protein clusters (OPCs) is largely dependent on the results of the reciprocal BLAST (basic local alignment search tool) hits among genomes. The BLAST algorithm is very efficient and fast, but it is very difficult to get optimal solution among phylogenetically distant species because the genomes with large evolutionary distance typically have low similarity in their protein sequences. To reduce the false positives in the OPCs, thresholding is often employed on the BLAST scores. However, the thresholding also eliminates large numbers of true positives as the orthologs from distant species likely have low BLAST scores. To rectify this problem, we introduce a new hybrid method combining the Recursive and the Markov CLuster (MCL) algorithms without using the BLAST thresholding. In the first step, we use InParanoid to produce n(n−1)/2 ortholog tables from n genomes. After combining all the tables into one, our clustering algorithm clusters ortholog pairs recursively in the table. Then, our method employs MCL algorithm to compute the clusters and refines the clusters by adjusting the inflation factor. We tested our method using six different genomes and evaluated the results by comparing against Kegg Orthology (KO) OPCs, which are generated from manually curated pathways. To quantify the accuracy of the results, we introduced a new intuitive similarity measure based on our Least‐move algorithm that computes the consistency between two OPCs. We compared the resulting OPCs with the KO OPCs using this measure. We also evaluated the performance of our method using InParanoid as the baseline approach. The experimental results show that, at the inflation factor 1.3, we produced 54% more orthologs than InParanoid sacrificing a little less accuracy (1.7% less) than InParanoid, and at the factor 1.4, produced not only 15% more orthologs than InParanoid but also a higher accuracy (1.4% more) than InParanoid. Proteins 2008. © 2007 Wiley‐Liss, Inc.
Unstructured intermediate states in single protein force experiments
Authors: Junier Ivan , Ritort Felix 
Published: November 2007

AbstractRecent single‐molecule force measurements on single‐domain proteins have highlighted a three‐state folding mechanism where a stabilized intermediate state ($ {\cal I} $) is observed on the folding trajectory between the stretched state and the native state. Here we investigate on‐lattice protein‐like heteropolymer models that lead to a three‐state mechanism and show that force experiments can be useful to determine the structure of $ {\cal I} $. We have mostly found that $ {\cal I} $ is composed of a core stabilized by a high number of native contacts, plus an unstructured extended chain. The lifetime of $ {\cal I} $ is shown to be sensitive to modifications of the protein that spoil the core. We then propose three types of modifications–point mutations, cuts, and circular permutations–aiming at: (1) confirming the presence of the core and (2) determining its location, within one amino acid accuracy, along the polypeptide chain. We also propose force jump protocols aiming to probe the on/off‐pathway nature of $ {\cal I} $. Proteins 2008. © 2007 Wiley‐Liss, Inc.
New insights of membrane environment effects on MscL channel mechanics from theoretical approaches
Authors: Debret Gaëlle , Valadié Hélène , Stadler Andreas Maximilian , Etchebest Catherine 
Published: November 2007

AbstractThe prokaryotic mechanosensitive channel of large conductance (MscL) is a remarkable integral membrane protein. During hypo‐osmotic shock, it responses to membrane tension through large conformational changes, that lead to an open state of the pore. The structure of the channel from Mycobacterium tuberculosis has been resolved in the closed state. Numerous experiments have attempted to trap the channel in its open state but they did not succeed in obtaining a structure. A gating mechanism has been proposed based on different experimental data but there is no experimental technique available to follow this process in atomic details. In addition, it has been shown that a decrease of the lipid bilayer thickness lowered MscL activation energy and stabilized a structurally distinct closed channel intermediate. Here, we use atomistic molecular dynamics simulations to investigate the effect of the lipid bilayer thinning on our model of the structure of the Escherichia coli. We thoroughly analyze simulations of the channel embedded in two pre‐equilibrated membranes differing by their hydrophobic tail length (DMPE and POPE). The MscL structure remains stable in POPE, whereas a distinct structural state is obtained in DMPE in response to hydrophobic mismatch. This latter is obtained by tilts and kinks of the transmembrane helices, leading to a widening and a diminution of the channel height. Part of these motions is guided by a competition between solvent and lipids for the interaction with the periplasmic loops. We finally conduct a principal component analysis of the simulation and compare anharmonic motions with harmonic ones, previously obtained from a coarse‐grained normal mode analysis performed on the same structural model. Significant similarities exist between low‐frequency harmonic motions and those observed with essential dynamics in DMPE. In summary, change in membrane thickness permits to accelerate the conformational changes involved in the mechanics of the E. coli channel, providing a closed structural intermediate en route to the open state. These results give clues for better understanding why the channel activation energy is lowered in a thinner membrane. Proteins 2008. © 2007 Wiley‐Liss, Inc.
Crystal structure of a secondary vitamin D3 binding site of milk β‐lactoglobulin
Authors: Yang Ming‐Chi , Guan Hong‐Hsiang , Liu Ming‐Yih , Lin Yih‐Hung , Yang Jinn‐Moon , Chen Wen‐Liang , Chen Chun‐Jung , Mao Simon J. T. 
Published: November 2007

Abstractβ‐lactoglobulin (β‐LG), one of the most investigated proteins, is a major bovine milk protein with a predominantly β structure. The structural function of the only α‐helix with three turns at the C‐terminus is unknown. Vitamin D3 binds to the central calyx formed by the β‐strands. Whether there are two vitamin D binding‐sites in each β‐LG molecule has been a subject of controversy. Here, we report a second vitamin D3 binding site identified by synchrotron X‐ray diffraction (at 2.4 Å resolution). In the central calyx binding mode, the aliphatic tail of vitamin D3 clearly inserts into the binding cavity, where the 3‐OH group of vitamin D3 binds externally. The electron density map suggests that the 3‐OH group interacts with the carbonyl of Lys‐60 forming a hydrogen bond (2.97 Å). The second binding site, however, is near the surface at the C‐terminus (residues 136–149) containing part of an α‐helix and a β‐strand I with 17.91 Å in length, while the span of vitamin D3 is about 12.51 Å. A remarkable feature of the second exosite is that it combines an amphipathic α‐helix providing nonpolar residues (Phe‐136, Ala‐139, and Leu‐140) and a β‐strand providing a nonpolar (Ile‐147) and a buried polar residue (Arg‐148). They are linked by a hydrophobic loop (Ala‐142, Leu‐143, Pro‐144, and Met‐145). Thus, the binding pocket furnishes strong hydrophobic force to stabilize vitamin D3 binding. This finding provides a new insight into the interaction between vitamin D3 and β‐LG, in which the exosite may provide another route for the transport of vitamin D3 in vitamin D3 fortified dairy products. Atomic coordinates for the crystal structure of β‐LG‐vitamin D3 complex described in this work have been deposited in the PDB (access code 2GJ5). Proteins 2008. © 2007 Wiley‐Liss, Inc.
Protein model quality assessment prediction by combining fragment comparisons and a consensus Cα contact potential
Authors: Zhou Hongyi , Skolnick Jeffrey 
Published: November 2007

AbstractIn this work, we develop a fully automated method for the quality assessment prediction of protein structural models generated by structure prediction approaches such as fold recognition servers, or ab initio methods. The approach is based on fragment comparisons and a consensus Cα contact potential derived from the set of models to be assessed and was tested on CASP7 server models. The average Pearson linear correlation coefficient between predicted quality and model GDT‐score per target is 0.83 for the 98 targets, which is better than those of other quality assessment methods that participated in CASP7. Our method also outperforms the other methods by about 3% as assessed by the total GDT‐score of the selected top models. Proteins 2008. © 2007 Wiley‐Liss, Inc.
X‐ray reflectivity study of a transcription‐activating factor‐derived peptide penetration into the model phospholipid monolayers
Authors: Tae Giyoong , Yang Hosung , Shin Kwanwoo , Satija Sushil K. , Torikai Naoya 
Published: November 2007

AbstractThe penetration of a transcription‐activating factor (TAT)‐derived, cell‐penetration peptide onto 1,2‐dipalmitoyl‐sn‐glycero‐3‐phosphocholine (DPPC) or 1,2‐dipalmitoyl‐sn‐glycero‐3‐[phospho‐L‐serine] (DPPS) monolayer on phosphate‐buffered saline subphase was characterized. The surface area at the target pressure increased noticeably by the peptide penetration from the subphase to the phospholipid monolayer, which might suggest a direct penetration of the peptide across the pure phospholipid bilayer membrane. Interestingly, the more significant area increase at 35 mN/m was monitored from DPPC monolayer, contrary to the simple charge interaction: the net neutral DPPC, the net‐negative DPPS, and the positive TAT‐derived peptides (TDP). X‐ray reflectivity measurements as well as the molecular area from π (surface pressure)‐A (area) isotherms suggest that the packing density of DPPS at the target pressure is too high to allow the effective penetration of the peptide into the monolayer and the positively charged peptides can be entrapped at the negative electrostatic well of DPPS headgroup layer, leading to the simple adsorption on the DPPS monolayer instead of penetration into it. Thus, more penetration with less adsorption of the peptide is induced by DPPC monolayer than DPPS monolayer. Copyright © 2007 European Peptide Society and John Wiley & Sons, Ltd.
Intersubband transitions in a biased superlattice: THz gain and surface mode
Authors: Vasko F. T. , Hernandez‐Cabrera A. , Aceituno P. 
Published: November 2007

AbstractIntersubband response in a biased superlattice with equipopulated levels is studied within the tight‐binding approximation and the complex dielectric permittivity is calculated beyond the Born approximation for a wide spectral region. The low‐frequency enhancement of the dispersion of permittivity is found and the conditions to obtain the stimulated emission regime is estimated. The enhancement of the emission due to the THz waveguide effect is also considered for the cases of the BSL placed between ideal metallic mirrors, the free‐standing BSL, and BSL at a vacuum‐dielectric interface. An appearance of the localized THz mode is described for the last case. (© 2008 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Femtosecond pump‐probe studies of carrier transport and gain dynamics in quantum cascade lasers
Authors: Choi Hyunyong , Diehl Laurent , Giovannini Marcella , Faist Jérôme , Capasso Federico , Norris Theodore B. 
Published: November 2007

AbstractTime‐resolved pump‐probe differential transmission measurements have been performed on various sets of quantum cascade lasers below and above threshold. Bias‐, temperature‐, and polarization dependent studies enable a comprehensive understanding of the gain dynamics to be possible in terms of tunneling, transport, and coupling with the intra‐cavity photon density. (© 2008 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)