bluuebunny/crossref_metadata_2025 huggingface dataset:
Are today’s authoritarian leaders doomed to be indicted when they leave office? The Russian and other post-Soviet cases
Authors: Shlapentokh Vladimir
Published: November 2006

The attitudes of leaders toward their personal future are very important to domestic and international politics. These views are particularly vital in the case of leaders of nondemocratic regimes who could face legal prosecution for their corrupt acts or violations of human rights in their own country and abroad. In spite of these fears, however, the leaders in many authoritarian societies trespass laws, both domestic and international, in order to preserve their power and enrich their families. They expose themselves to the danger of the prosecution after they leave office or lose control of the regime. In this context, the author pays special attention to Vladimir Putin’s political future and to the developments in Russia, which favor and disfavor his continued stay in power after 2008.
A rare anatomical variation of the spinal accessory nerve
Authors: Iseri M , Ustundag E , Aydın Ö
Published: November 2006

Considerable inter- and intra-individual anatomical differences can be observed during neck dissections. In this case report, we describe an unusual relationship of the accessory nerve to the internal jugular vein.
Transient, synobduction exhumation of Zagros blueschists inferred from P‐T, deformation, time, and kinematic constraints: Implications for Neotethyan wedge dynamics
Authors: Agard P. , Monié P. , Gerber W. , Omrani J. , Molinaro M. , Meyer B. , Labrousse L. , Vrielynck B. , Jolivet L. , Yamato P.
Published: November 2006

We present the first P‐T, deformation time, and kinematic constraints on the only known blueschist facies rocks (BS) present in the Zagros (Hajiabad area). The BS were underplated below the Sanandaj‐Sirjan zone and crop out as kilometer‐scale bodies within extensive colored melange units marking discontinuously the Neotethyan suture zone. P‐T estimates point to high‐pressure/low‐temperature (HP‐LT) conditions around 11 kbar and 520–530°C for the majority of BS, along a ∼15°C km−1 gradient. Some exotic blocks in matrix serpentinite reached 17–18 kbar at ∼500°C. In situ laser probe 40Ar‐39Ar radiometric age constraints on phengite cluster between 85 and 95 Ma and suggest that (1) synconvergence exhumation of Zagros BS from 35–50 km to depths <15–20 km was accomplished before 80 Ma, (2) BS exhumation corresponded to a transient process with respect to the long‐lived subduction beneath Iran (∼150–35 Ma), and (3) age constraints for Zagros BS are 5–10 Myr older than for the nearby Oman HP‐LT rocks and broadly coincide with obduction processes in the region (circa 95–70 Ma). We propose that the mechanical coupling across the Neotethyan subduction zone (NSZ) beneath Iran was modified by the large‐scale plate rearrangement accompanying obduction, allowing for a short‐lived exhumation of Zagros BS. Exhumation ceased at the end of obduction, when subduction of the Arabian continental margin stopped. Kinematic calculations suggest that convergence velocities across the NSZ likely doubled (to ∼5–6 cm yr−1) during the period 118–85 Ma, so that BS exhumation may have been promoted by a combination of obduction movements and increased convergence velocities.
Dynamics of Kuroshio path variations in a high‐resolution general circulation model
Authors: Tsujino Hiroyuki , Usui Norihisa , Nakano Hideyuki
Published: November 2006

A long‐lived (2‐year) typical large meander (LM) path of the Kuroshio is reproduced in a high‐resolution general circulation model (GCM) simulation with realistic topography, and the life cycle (formation, maintenance, and disappearance) of the LM is studied. The formation of the LM is triggered by a pair of upper layer anticyclonic and cyclonic eddies on the Kuroshio, with the cyclonic one on the downstream side. Upon reaching the western side of the Shikoku Basin south of Japan these anomalies induce a lower layer anticyclonic eddy. They enhance each other while they are carried eastward by the Kuroshio. Specifically, the southward flow on the eastern side of the lower anticyclonic eddy carries the upper cold cyclonic eddy offshore, resulting in the southward deflection of the Kuroshio path (large meander). These processes can be understood as a growth of baroclinic instability. A stationary LM is established when the westward tendency, caused by the beta effect owing to the large meridional displacement, counterbalances the eastward tendency, caused by the combination of advection and vortex induction owing to the curvature of the Kuroshio path. Large‐scale disturbances from the upstream tend to strengthen the LM through baroclinic energy conversion. In contrast, small‐scale disturbances from the upstream grow locally along the meandering Kuroshio front through baroclinic energy conversion. They extract cold waters from the cold cyclonic eddy of the LM as they flow away to the east. The horizontal extent of the cold cyclonic eddy is reduced, and the meander is carried eastward since the advection effect dominates over the beta effect that weakens as a result of the smaller meridional extent.
Surface vibrational structure at alkane liquid/vapor interfaces
Authors: Esenturk Okan , Walker Robert A.
Published: November 2006

Broadband vibrational sum frequency spectroscopy (VSFS) has been used to examine the surface structure of alkane liquid/vapor interfaces. The alkanes range in length from n-nonane (C9H20) to n-heptadecane (C17H36), and all liquids except heptadecane are studied at temperatures well above their bulk (and surface) freezing temperatures. Intensities of vibrational bands in the CH stretching region acquired under different polarization conditions show systematic, chain length dependent changes. Data provide clear evidence of methyl group segregation at the liquid/vapor interface, but two different models of alkane chain structure can predict chain length dependent changes in band intensities. Each model leads to a different interpretation of the extent to which different chain segments contribute to the anisotropic interfacial region. One model postulates that changes in vibrational band intensities arise solely from a reduced surface coverage of methyl groups as alkane chain length increases. The additional methylene groups at the surface must be randomly distributed and make no net contribution to the observed VSF spectra. The second model considers a simple statistical distribution of methyl and methylene groups populating a three dimensional, interfacial lattice. This statistical picture implies that the VSF signal arises from a region extending several functional groups into the bulk liquid, and that the growing fraction of methylene groups in longer chain alkanes bears responsibility for the observed spectral changes. The data and resulting interpretations provide clear benchmarks for emerging theories of molecular structure and organization at liquid surfaces, especially for liquids lacking strong polar ordering.
Fast noniterative orbital localization for large molecules
Authors: Aquilante Francesco , Bondo Pedersen Thomas , Sánchez de Merás Alfredo , Koch Henrik
Published: November 2006

We use Cholesky decomposition of the density matrix in atomic orbital basis to define a new set of occupied molecular orbital coefficients. Analysis of the resulting orbitals (“Cholesky molecular orbitals”) demonstrates their localized character inherited from the sparsity of the density matrix. Comparison with the results of traditional iterative localization schemes shows minor differences with respect to a number of suitable measures of locality, particularly the scaling with system size of orbital pair domains used in local correlation methods. The Cholesky procedure for generating orthonormal localized orbitals is noniterative and may be made linear scaling. Although our present implementation scales cubically, the algorithm is significantly faster than any of the conventional localization schemes. In addition, since this approach does not require starting orbitals, it will be useful in local correlation treatments on top of diagonalization-free Hartree-Fock optimization algorithms.
Nonlinear breakup of a coaxial liquid jet in a swirling gas stream
Authors: Ibrahim Ashraf A. , Jog Milind A.
Published: November 2006

Nonlinear asymmetric breakup of a liquid jet exposed to a swirling gas stream is investigated by a perturbation expansion technique with the initial amplitude of the disturbance as the perturbation parameter. The effects of gas-to-liquid axial velocity ratio and gas swirl number on the liquid jet instability and breakup length have been studied. The breakup length predictions show good agreement with the available empirical correlations for liquid jet breakup in still gas as well as jet breakup in a co-flowing gas stream. Earlier linear analyses have predicted that the gas swirl has a stabilizing influence on the jet and that the axisymmetric disturbance is the most unstable disturbance compared to the helical modes. In contrast, experimental studies report that a swirl imparted on the surrounding gas makes the jet unstable, and at high gas swirl the jet disintegrates through an explosive breakup. The present nonlinear temporal analysis correctly captures the destabilizing effect of the gas swirl. With increasing gas swirl number, the helical modes become dominant and the transition to subsequent higher helical mode is achieved with smaller increments in the gas swirl number. The gas swirl number for transition to a highly asymmetric breakup with a high circumferential wave number (n=5) is found to vary as the inverse of the square root of the gas-to-liquid momentum ratio when the gas-to-liquid momentum ratio is less than 1. The jet breakup length decreases with an increase in the gas-to-liquid axial velocity ratio and the gas swirl number.
Geometric effects on the inelastic deformation of metal nanowires
Authors: Ji Changjiang , Park Harold S.
Published: November 2006

This letter addresses the direct effect that geometry has in controlling the mechanisms of inelastic deformation in metal nanowires. By performing atomistic simulations of the tensile deformation of ⟨100⟩∕{100} hollow copper nanowires (nanoboxes), the authors find that the nanoboxes deform in an unexpected twinning-dominated mode; the nonsquare wall geometries of the nanoboxes bias the deformation by allowing the larger transverse {100} surfaces to reduce their area through twinning by reorienting to a lower energy {111} surface. Additional analyses on solid nanowires with nonsquare cross sections confirm that geometry can be utilized to engineer the mechanical behavior and properties of nanomaterials.
Flow dynamics and forces associated with a cylinder rolling along a wall
Authors: Stewart Bronwyn , Hourigan Kerry , Thompson Mark , Leweke Thomas
Published: November 2006

The wake flow structures and the drag force for a cylinder rolling along a wall without slipping were calculated for the Reynolds number range 20<Re<200, covering the two-dimensional shedding regime. Time-dependent numerical computations show the wake undergoes a steady to periodic shedding transition between 85<Re<90. The Strouhal number varies only weakly at higher Reynolds number, and is a factor of 3–4 lower than for an isolated rotating or nonrotating body. Also, within this shedding regime, the wake is characterized by counter-rotating vortex pairs, which propagate away from the wall via mutual induction. These pairs are formed as compact vortex structures from the top separating shear layer induce secondary vorticity at the wall, which is pulled up from the boundary to form the semidiscrete flow structures. Over both the steady and unsteady regimes, the (time-mean) recirculation length and drag are quantified.
Hierarchical surface rough ordered Au particle arrays and their surface enhanced Raman scattering
Authors: Duan Guotao , Cai Weiping , Luo Yuanyuan , Li Yue , Lei Yong
Published: November 2006

A simple, effective, and low-cost method is presented to fabricate an ordered Au particle array with hierarchical surface roughness on an indium tin oxide substrate based on an ordered alumina through-pore template, induced by solution dipping on colloidal monolayer, using an electrochemical deposition strategy. The array consists of periodically arranged and isolated Au microparticles, which show nanoscaled surface roughness. Importantly, this hierarchically rough particle array exhibits strong surface-enhanced Raman scattering effect using rhodamine 6G as probe molecules, associated with its surface geometry. Such structure could be useful, e.g., in sensors, biotechnology, and nanodevices.
Electron trapping and inversion layer formation in photoexcited metal-insulator-poly(3-hexylthiophene) capacitors
Authors: Taylor D. M. , Drysdale J. A. , Torres I. , Fernández O.
Published: November 2006

Photocapacitance measurements are reported on metal-insulator-semiconductor (MIS) capacitors employing polyimide (PI) or polysilsesquioxane (PSQ) as the gate insulator and poly(3-hexylthiophene) as the active semiconductor. By stressing devices into depletion while simultaneously irradiating with light of energy exceeding the semiconductor band gap, photogenerated electrons become trapped at the insulator/semiconductor interface or possibly in bulk insulator states. Additionally for the PSQ device, evidence is provided for the formation of a photogenerated inversion layer at the interface. The time dependence of electron detrapping in the PI case is similar to that observed for accumulation stress instability in organic MIS devices.
White organic light-emitting diodes with fine chromaticity tuning via ultrathin layer position shifting
Authors: Choukri Hakim , Fischer Alexis , Forget Sébastien , Chénais Sébastien , Castex Marie-Claude , Adès Dominique , Siove Alain , Geffroy Bernard
Published: November 2006

Nondoped white organic light-emitting diodes using an ultrathin yellow-emitting layer of rubrene (5,6,11,12-tetraphenylnaphtacene) inserted on either side of the interface between a hole-transporting 4,4′-bis[N-(1-naphtyl)-N-phenylamino]biphenyl (α-NPB) layer and a blue-emitting 4,4′-bis(2,2′-diphenylvinyl)-1,1′-biphenyl (DPVBi) layer are described. Both the thickness and the position of the rubrene layer allow fine chromaticity tuning from deep blue to pure yellow via bright white with CIE coordinates (x=0.33, y=0.32), an ηext of 1.9%, and a color rendering index of 70. Such a structure also provides an accurate sensing tool to measure the exciton diffusion length in both DPVBi and NPB (8.7 and 4.9nm, respectively).
Structure of a heparin-dependent complex of Hedgehog and Ihog
Authors: McLellan Jason S. , Yao Shenqin , Zheng Xiaoyan , Geisbrecht Brian V. , Ghirlando Rodolfo , Beachy Philip A. , Leahy Daniel J.
Published: November 2006

Hedgehog (Hh) signaling molecules mediate key tissue-patterning events during animal development, and inappropriate activation of Hh signaling in adults has been associated with human cancers. Recently, a conserved family of type I integral membrane proteins required for normal response to the Hh signal was discovered. One member of this family, Ihog (interference hedgehog), functions upstream or at the level of Patched (Ptc), but how Ihog participates in Hh signaling remains unclear. Here, we show that heparin binding induces Ihog dimerization and is required to mediate high-affinity interactions between Ihog and Hh. We also present crystal structures of a Hh-binding fragment of Ihog, both alone and complexed with Hh. Heparin is not well ordered in these structures, but a basic cleft in the first FNIII domain of Ihog (IhogFn1) is shown by mutagenesis to mediate heparin binding. These results establish that Hh directly binds Ihog and provide the first demonstration of a specific role for heparin in Hh responsiveness.
Loss of Caspase-9 Reveals Its Essential Role for Caspase-2 Activation and Mitochondrial Membrane Depolarization
Authors: Samraj Ajoy K. , Sohn Dennis , Schulze-Osthoff Klaus , Schmitz Ingo
Published: November 2006

Caspase-9 plays an important role in apoptosis induced by genotoxic stress. Irradiation and anticancer drugs trigger mitochondrial outer membrane permeabilization, resulting in cytochrome c release and caspase-9 activation. Two highly contentious issues, however, remain: It is unclear whether the loss of the mitochondrial membrane potential ΔΨMcontributes to cytochrome c release and whether caspases are involved. Moreover, an unresolved question is whether caspase-2 functions as an initiator in genotoxic stress-induced apoptosis. In the present study, we have identified a mutant Jurkat T-cell line that is deficient in caspase-9 and resistant to apoptosis. Anticancer drugs, however, could activate proapoptotic Bcl-2 proteins and cytochrome c release, similarly as in caspase-9–proficient cells. Interestingly, despite these alterations, the cells retained ΔΨM. Furthermore, processing and enzyme activity of caspase-2 were not observed in the absence of caspase-9. Reconstitution of caspase-9 expression restored not only apoptosis but also the loss of ΔΨMand caspase-2 activity. Thus, we provide genetic evidence that caspase-9 is indispensable for drug-induced apoptosis in cancer cells. Moreover, loss of ΔΨMcan be functionally separated from cytochrome c release. Caspase-9 is not only required for ΔΨMloss but also for caspase-2 activation, suggesting that these two events are downstream of the apoptosome.
Kidins220/ARMS Is Transported by a Kinesin-1–based Mechanism Likely to be Involved in Neuronal Differentiation
Authors: Bracale Aurora , Cesca Fabrizia , Neubrand Veronika E. , Newsome Timothy P. , Way Michael , Schiavo Giampietro
Published: November 2006

Kinase D-interacting substrate of 220 kDa/ankyrin repeat-rich membrane spanning (Kidins220/ARMS) is a conserved membrane protein mainly expressed in brain and neuroendocrine cells, which is a downstream target of the signaling cascades initiated by neurotrophins and ephrins. We identified kinesin light chain 1 (KLC1) as a binding partner for Kidins220/ARMS by a yeast two-hybrid screen. The interaction between Kidins220/ARMS and the kinesin-1 motor complex was confirmed by glutathione S-transferase-pull-down and coimmunoprecipitation experiments. In addition, Kidins220/ARMS and kinesin-1 were shown to colocalize in nerve growth factor (NGF)-differentiated PC12 cells. Using Kidins220/ARMS and KLC1 mutants, we mapped the regions responsible for the binding to a short sequence of Kidins220/ARMS, termed KLC-interacting motif (KIM), which is sufficient for the interaction with KLC1. Optimal binding of KIM requires a region of KLC1 spanning both the tetratricopeptide repeats and the heptad repeats, previously not involved in cargo recognition. Overexpression of KIM in differentiating PC12 cells impairs the formation and transport of EGFP-Kidins220/ARMS carriers to the tips of growing neurites, leaving other kinesin-1 dependent processes unaffected. Furthermore, KIM overexpression interferes with the activation of the mitogen-activated protein kinase signaling and neurite outgrowth in NGF-treated PC12 cells. Our results suggest that Kidins220/ARMS-positive carriers undergo a kinesin-1–dependent transport linked to neurotrophin action.
Three Ubiquitin Conjugation Sites in the Amino Terminus of the Dopamine Transporter Mediate Protein Kinase C–dependent Endocytosis of the Transporter
Authors: Miranda Manuel , Dionne Kalen R. , Sorkina Tatiana , Sorkin Alexander
Published: November 2006

Dopamine levels in the brain are controlled by the plasma membrane dopamine transporter (DAT). The amount of DAT at the cell surface is determined by the relative rates of its internalization and recycling. Activation of protein kinase C (PKC) leads to acceleration of DAT endocytosis. We have recently demonstrated that PKC activation also results in ubiquitylation of DAT. To directly address the role of DAT ubiquitylation, lysine residues in DAT were mutated. Mutations of each lysine individually did not affect ubiquitylation and endocytosis of DAT. By contrast, ubiquitylation of mutants carrying multiple lysine substitutions was reduced in cells treated with phorbol ester to the levels detected in nonstimulated cells. Altogether, mutagenesis data suggested that Lys19, Lys27, and Lys35 clustered in the DAT amino-terminus are the major ubiquitin-conjugation sites. The data are consistent with the model whereby at any given time only one of the lysines in DAT is conjugated with a short ubiquitin chain. Importantly, cell surface biotinylation, immunofluorescence and down-regulation experiments revealed that PKC-dependent internalization of multilysine mutants was essentially abolished. These data provide the first evidence that the ubiquitin moieties conjugated to DAT may serve as a molecular interface of the transporter interaction with the endocytic machinery.
Large Vestibular Aqueduct Syndrome: A Human Temporal Bone Study
Authors: Hirai Shigeo , Cureoglu Sebahattin , Schachern Patricia A. , Hayashi Hideo , Paparella Michael M. , Harada Tamotsu
Published: November 2006

Objectives/Hypothesis: Large vestibular aqueduct syndrome (LVAS) is one of the common causes of hearing loss (HL). All prior studies have reported some anomalies associated with LVAS by imaging techniques. This study was undertaken to determine prevalence of LVAS in our temporal bone (TB) collection and its relationship to other systemic or otologic anomalies.

Study Design: Retrospective, TB histopathologic study.

Methods: Anteroposterior diameters of internal (IA) and external (EA) apertures were measured in 40 normal TBs (40 cases). TBs were considered as large vestibular aqueduct (LVA) if width of apertures was 95% greater than “normals.” Systemic and otologic anomalies and histopathology of ears with LVAS were noted.

Result: Of 1,608 non‐“normal” TBs, 63 had LVA. There was negative correlation between IA and EA in 48 TBs with only enlarged IA. Fifteen TBs with enlarged EA always had enlarged IA and were therefore considered as LVAS. The most common pathologic condition was congenital heart anomaly. The most common syndrome or dysplasia was Mondini's. The most common anomalies of external and middle ears were dehiscent facial nerves, low set auricles, and ossicular deformities. Inner ear anomalies included modiolar deficiencies, hair cell loss, interscalar septum defects, and strial atrophy. There was no record of family history of HL, head injury, or craniofacial, branchial, or thyroidal abnormalities.

Conclusion: Because HL associated with LVAS may be attributed to other ear anomalies, it is important to investigate other inner ear problems and system diagnoses that may indicate a syndrome in patients with radiologically diagnosed LVAS.
Nasal Sound Analysis: A New Method for Evaluating Nasal Obstruction in Allergic Rhinitis
Authors: Tahamiler Rauf , Edizer Deniz Tuna , Canakcioglu Salih , Guvenc Melih Guven , Inci Ender , Dirican Ahmet
Published: November 2006

Objective: Current measurements of nasal obstruction are unreliable and may be improved with the development of new techniques. The effectiveness of odiosoft‐rhino (OR) in the evaluation of nasal obstruction was investigated in a blind comparison at a referral center, institutional practice.

Patients: Forty‐eight patients with perennial allergic rhinitis and 52 healthy subjects were studied. Nasal endoscopic examination, acoustic rhinometry (AR), and OR were performed and symptom scores compared.

Main Outcome Measure: Assessment of nasal blockage with OR method was the main outcome measure.

Results: Using the OR technique, significant differences were observed between the patient and control groups. OR data correlated with symptom scores and endoscopic examination. However, this was not observed with AR. A 15.5‐dB cutoff point for the left side and 14.5 dB cutoff point for the right side at the 2,000 to 4,000 Hz frequency interval resulted in 93.8% sensitivity and 92.3% specificity and 72.9% sensitivity and 80.8% specificity, respectively. A 8.5‐dB cutoff point for the left and right sides at the 4,000 to 6,000 Hz frequency interval resulted in 87.5% sensitivity and 80.8% specificity and 70.8% sensitivity and 78.8% specificity, respectively.

Conclusion: OR is a simple, noninvasive test for assessing nasal obstruction. The OR technique can detect nasal obstruction with high sensitivity and specificity, and these findings correlate with symptoms and physical examination.
Long‐Term Follow‐up of Hearing Loss in Children and Young Adults With Enlarged Vestibular Aqueducts: Relationship to Radiologic Findings and Pendred Syndrome Diagnosis
Authors: Colvin Ian B. , Beale Timothy , Harrop‐Griffiths Katherine
Published: November 2006

Objective: To describe the long‐term audiologic findings in pediatric patients with enlarged vestibular aqueducts (EVAs). The relationship between the hearing loss (HL) and the dimensions of the EVA, enlarged endolymphatic duct (EED), or enlarged endolymphatic sac (EES) was also investigated. The influence of a Pendred syndrome (PS) diagnosis on the audiologic phenotype was also examined.

Study Design: Retrospective analysis of case notes and imaging records, including measurement of the dimensions of the EVA, EED, and EES.

Setting: Tertiary referral center.

Patients: Twenty‐seven patients (21 female, 6 male) had an EVA in at least one ear. Eighty‐five percent had bilateral enlargements. Median age at onset of follow‐up was 5.0 years, and median follow‐up was 9.7 years.

Main Outcome Measures: Hearing thresholds at the start and end of follow‐up, rate of progression of HL, history of sudden drops in hearing.

Results: All ears with an EVA had HL. Average HL at the start and end of follow‐up was severe. Thirty‐seven percent of patients had progressive HL, and 33% reported sudden drops in hearing. Progression was significantly associated with a history of sudden drops. PS patients had worse hearing at the end of follow‐up as compared with nonsyndromic patients. There was no evidence of a relationship between the dimensions of the EVA, EED, or EES and the severity or progression of HL.

Conclusions: Patients with EVAs should be advised to avoid known trigger factors for sudden drops in hearing (e.g., minor head trauma). A diagnosis of PS may be associated with a worse audiologic prognosis.
Lymphovascular Invasion is Associated With Lateral Cervical Lymph Node Metastasis in Papillary Thyroid Carcinoma
Authors: Kim Jung Min , Kim Tae Yong , Kim Won Bae , Gong Gyungyup , Kim Seong Chul , Hong Suck Joon , Shong Young Kee
Published: November 2006

Objectives: The objective of this retrospective study to evaluate whether lymphovascular invasion (LVI) is associated with lateral cervical lymph node metastasis and tumor recurrence in papillary thyroid carcinoma (PTC).

Methods: We evaluated the medical records of patients with PTC who had undergone total thyroidectomy and subsequent 131I remnant ablation at Asan Medical Center, Seoul, Korea, from January 1997 thorough December 2000.

Results: A total of 662 patients (585 women and 77 men; mean age, 44.8 years) with PTC were enrolled in the study. Of these patients, 33 were found to have LVI. We found a significant association between LVI and lateral cervical lymph node metastasis at the time of initial surgery (P = .001). Multivariate analyses adjusting for clinicopathologic parameters known to predict recurrence such as age, gender, tumor size, extrathyroid extension, and multifocality also showed a significant association between LVI and lateral cervical lymph node metastasis. For the 633 patients without distant metastasis at the time of initial surgery, LVI was also significantly associated with tumor recurrence during the follow‐up period (median, 68 months; range, 3–108 months): 29% versus 13.6% for patients with and without LVI, respectively (P = .048 by log‐rank test). However, this association was lost on multivariate analyses adjusting for conventional clinicopathologic predictors of recurrence.

Conclusions: In patients with PTC, LVI is associated with lateral cervical lymph node metastasis and clinical recurrence.
Phosphorylation and functions of the RNA polymerase II CTD
Authors: Phatnani Hemali P. , Greenleaf Arno L.
Published: November 2006

The C-terminal repeat domain (CTD), an unusual extension appended to the C terminus of the largest subunit of RNA polymerase II, serves as a flexible binding scaffold for numerous nuclear factors; which factors bind is determined by the phosphorylation patterns on the CTD repeats. Changes in phosphorylation patterns, as polymerase transcribes a gene, are thought to orchestrate the association of different sets of factors with the transcriptase and strongly influence functional organization of the nucleus. In this review we appraise what is known, and what is not known, about patterns of phosphorylation on the CTD of RNA polymerases II at the beginning, the middle, and the end of genes; the proposal that doubly phosphorylated repeats are present on elongating polymerase is explored. We discuss briefly proteins known to associate with the phosphorylated CTD at the beginning and ends of genes; we explore in more detail proteins that are recruited to the body of genes, the diversity of their functions, and the potential consequences of tethering these functions to elongating RNA polymerase II. We also discuss accumulating structural information on phosphoCTD-binding proteins and how it illustrates the variety of binding domains and interaction modes, emphasizing the structural flexibility of the CTD. We end with a number of open questions that highlight the extent of what remains to be learned about the phosphorylation and functions of the CTD.
Canonical notch signaling functions as a commitment switch in the epidermal lineage
Authors: Blanpain Cédric , Lowry William E. , Pasolli H. Amalia , Fuchs Elaine
Published: November 2006

Mammalian epidermis consists of a basal layer of proliferative progenitors that gives rise to multiple differentiating layers to provide a waterproof envelope covering the skin surface. To accomplish this, progenitor cells must detach from the basal layer, move upward, and execute a terminal differentiation program consisting of three distinct stages: spinous, granular layer, and stratum corneum. Notch signaling has been implicated in late stages of differentiation, but the commitment switch remains unknown. Here we show with loss and gain-of-function studies that active Notch intracellular domain (NICD) and its obligate canonical signaling partner RBP-J act at the basal/suprabasal juncture to induce spinous and down-regulate basal fate. Spinous layers are absent in RBP-J conditional null epidermis and expanded when Notch1 signaling is elevated transgenically in epidermis. We show that RBP-J is essential for mediating both spinous gene activation and basal gene repression. In contrast, the NICD/RBP-J target gene Hes1 is expressed in spinous layers and mediates spinous gene induction but not basal gene repression. These data uncover an early role for RBP-J and Notch in commitment of epidermal cells to terminally differentiate and reveal that spinous gene induction is mediated by a Hes1-dependent mechanism, while basal gene repression occurs independently of Hes1.
Trifluralin herbicide‐induced resistance of melon to fusarium wilt involves expression of stress‐ and defence‐related genes
Authors: LOTAN‐POMPAN MAYA , COHEN RON , YARDEN ODED , PORTNOY VITALY , BURGER YOSEF , KATZIR NURIT
Published: November 2006

To identify genes involved in trifluralin herbicide‐induced resistance of melon to Fusarium oxysporum f. sp. melonis, suppression subtractive hybridization (SSH) and cDNA‐amplified fragment‐length polymorphism (cDNA‐AFLP) were used. A total of 123 clones—60 of which have never been isolated from melon—were isolated, sequenced and annotated. A significant proportion (35%) of the total 123 clones exhibited similarity to genes that have been formerly described as stress‐ or defence‐related. Thirty‐two selected clones were subjected to a detailed expression analysis, one‐third of which were found to be up‐regulated in response to trifluralin treatment and/or fusarium inoculation. The putative roles of seven of these clones in stress are discussed. Furthermore, the expression of four stress‐related and up‐regulated genes was enhanced when the plants were subjected to salinity stress, suggesting that trifluralin induces a general stress response which protects the plant against fusarium wilt.
Preceding immunosuppressive therapy with antithymocyte globulin and ciclosporin increases the incidence of graft rejection in children with aplastic anaemia who underwent allogeneic bone marrow transplantation from HLA‐identical siblings
Authors: Kobayashi Ryoji , Yabe Hiromasa , Hara Junichi , Morimoto Akira , Tsuchida Masahiro , Mugishima Hideo , Ohara Akira , Tsukimoto Ichiro , Kato Koji , Kigasawa Hisato , Tabuchi Ken , Nakahata Tatsutoshi , Ohga Shoichi , Kojima Seiji ,   the Japan Childhood Aplastic Anemia Study Group
Published: November 2006

The incidence of graft rejection was determined in 66 children with acquired aplastic anaemia (AA) following bone marrow transplantation (BMT) from a related donor. Eleven of 65 evaluable patients experienced either early or late rejection. Multivariate analysis identified previous immunosuppressive therapy with antithymocyte‐globulin (ATG) and ciclosporin (CsA) as a risk factor for graft rejection (relative risk: 16·6, P = 0·001). Patients who received ATG and CsA had a significantly lower probability of failure‐free survival than those who did not (69·7 ± 6·2% vs. 87·9 ± 8·0%, P = 0·044). These results suggest that BMT should be instituted immediately in children with severe AA who have human leucocyte antigen‐identical siblings.
Probiotics in the treatment of Japanese cedar pollinosis: a double‐blind placebo‐controlled trial
Authors: Xiao J.‐Z. , Kondo S. , Yanagisawa N. , Takahashi N. , Odamaki T. , Iwabuchi N. , Miyaji K. , Iwatsuki K. , Togashi H. , Enomoto K. , Enomoto T.
Published: November 2006

Background
Probiotic bacteria may be effective in the treatment of allergic inflammation and food allergy, but efficacy and underlying mechanisms remain unclear.

Objective
The present study investigated the effects of probiotic strain Bifidobacterium longum BB536 in the treatment of Japanese cedar pollinosis (JCPsis).

Methods
In a randomized, double‐blind, placebo‐controlled trial, 44 JCPsis subjects received BB536 or placebo for 13 weeks during the pollen season. Subjective symptoms and self‐care measures were recorded daily and blood samples were taken before and during intervention to measure blood levels of parameters related to JCPsis.

Results
BB536 intake was associated with a significant reduction in number of subjects prematurely terminated due to severe symptoms and pollinosis medication (P=0.0057 vs. placebo group). Comparison of subjective symptom scores indicated significant decreases in rhinorrhea, nasal blockage and composite scores in the BB536 group compared with the placebo group. Comparison of medical scores showed marked improvements in all symptoms on BB536 intake. A T‐helper type 2 (Th2)‐skewed immune response occurring along with pollen dispersion was observed. BB536 significantly suppressed increases in plasma thymus‐ and activation‐regulated chemokine and tended to suppress elevations of Japanese cedar pollen (JCP)‐specific IgE.

Conclusion
These results suggest the efficacy of BB536 in relieving JCPsis symptoms, probably through the modulation of Th2‐skewed immune response.
Ultrafine but not fine particulate matter causes airway inflammation and allergic airway sensitization to co‐administered antigen in mice
Authors: De Haar C. , Hassing I. , Bol M. , Bleumink R. , Pieters R.
Published: November 2006

Background
Airborne particulate matter (PM) is an important factor associated with the enhanced prevalence of respiratory allergy. The PM adjuvant activity on allergic sensitization is a possible mechanism of action involved, and the induction of airway inflammation is suggested to be of importance in PM‐induced adjuvant activity.

Objective
Because differently sized PM have different toxic potentials, we studied the role of particle size in the induction of airway inflammation and allergic sensitization. This was done using fine (0.250 and 0.260 μm) and ultrafine (0.029 and 0.014 μm) titanium dioxide (TiO2) and carbon black particles (CBP) with known differences in airway toxicity.

Methods
Mice were intranasally exposed to ovalbumin (OVA) alone or in combination with one of the different particles. The induction of airway inflammation and the immune adjuvant activity were studied in the lungs and lung‐draining peribronchial lymph nodes (PBLN) at day 8. OVA‐specific antibodies were measured at day 21, and the development of allergic airway inflammation was studied after OVA challenges (day 28).

Results
When administered at the same total particle mass (200 μg), exposure to ultrafine TiO2 and CBP‐induced airway inflammation, and had immune adjuvant activity. The latter was shown by increasing both the PBLN cell numbers and the production of OVA‐specific T‐helper type 2 (Th2) cytokines (IL‐4, IL‐5, IL‐10 and IL‐13). Whereas OVA‐specific IgE and IgG1 levels in serum were only increased in animals exposed to the ultrafine TiO2, allergic airway inflammation could be detected in both ultrafine TiO2‐and CBP‐treated groups after challenges with OVA.

Conclusion
Our data show that only the ultrafine particles, with a small diameter and a large total surface area/mass, cause airway inflammation and have immune adjuvant activity in the current model supporting the hypothesis that particle toxicity is site‐dependent and related to adjuvant activity.
Genetic selection for resistance or susceptibility to oral tolerance imparts correlation to both Immunoglobulin E level and mast cell number phenotypes with a profound impact on the atopic potential of the individual
Authors: Da Silva M. F. S. , Nóbrega A. , Ribeiro R. C. , Levy M. S. , Ribeiro O. G. , Tambourgi D. V. , Sant'Anna D. A. , Da Silva A. C.
Published: November 2006

Background
Immunological oral tolerance is being studied with great interest due to its therapeutic potential in allergy and autoimmunity processes, although the cellular and molecular mechanisms linking these different phenomena remain elusive. In the present study, two mouse lines with extreme phenotypes for susceptibility [TS Line] or resistance [TR Line] to oral tolerance and their [TS × TR]F2 segregants were used in order to evaluate the impact of these traits on the atopic potential of the individuals.

Objective
Demonstrate whether the tr and ts genes, cumulated during 18 generations of bidirectional genetic selection, influence expression of two important immunobiological traits (IgE and mast cell) critical to allergic response.

Methods
Mice with extreme phenotypes for oral tolerance to ovalbumin (OVA), produced by assortative mating (TS and TR Line), and their (TS × TR)F2 segregating were used. Serum IgE levels assayed by ELISA, and mastocytes counted with toluidine blue staining were evaluated in naïve mice. Anaphylaxis was induced by intravenous injection of OVA, intestinal inflammation by oral administration of OVA 7 days after immunization, and pulmonary inflammation by intranasal and nebulization OVA challenges. Specific IgE was dosed by passive cutaneous anaphylaxis.

Results
The naïve TS mice have a 20‐fold lower serum IgE level and two‐ to threefold diminished mast cell numbers in mucosal sites, when compared with TR‐mice, which were highly susceptible to allergic inflammation and anaphylactic shock. The associations of oral tolerance, serum IgE levels and mast cell numbers in naïve animals were confirmed analysing the simultaneous presence of these traits in individuals of a [TS × TR]F2‐segregating population.

Conclusion
The results suggest that the complex of genes controlling TS and TR phenotypes play a main role in the regulation of the atopic potential of the individual. The studies of these traits in interline F2 segregants demonstrated a co‐segregation of TS and TR phenotypes with IgE responsiveness and mast cell numbers. Thus, the opposite capacity of the genetically modified mice may be involved in co‐adaptative mechanisms reflecting a dynamic relation between gene frequencies in a natural population. These correlations give circumstantial evidence to support clinical applications of oral tolerance in allergic and autoimmune diseases.
Cytochrome P450‐dependent metabolism of midazolam in hepatic microsomes from chickens, turkeys, pheasant and bobwhite quail
Authors: CORTRIGHT K. A. , CRAIGMILL A. L.
Published: November 2006

In vitroputative cytochrome P450 3A mediated activity, and inhibition thereof, were measured in four avian species using midazolam (MDZ) as a substrate and ketoconazole as an inhibitor. All species produced 1‐hydroxymidazolam (1‐OH MDZ) to a much greater extent than 4‐hydroxymidazolam (4‐OH MDZ). CalculatedVmaxapparentvalues for formation of 1‐OH MDZ were 117 ± 17, 239 ± 108, 437 ± 168, and 201 ± 55 pmol/mg protein*min andKmapparentvalues were 2.1 ± 0.8, 2.4 ± 1.6, 6.7 ± 5.1 and 3.2 ± 2.1 μmfor chicken, turkey, pheasant and bobwhite quail, respectively. For the formation of 4‐OH MDZ theVmaxapparentvalues were 21 ± 10, 94 ± 46, 144 ± 112, and 68 ± 30 pmol/mg protein*min andKmapparentvalues for 4‐OH MDZ formation were 12.4 ± 10.1, 18.0 ± 10.8, 38.6 ± 34.7 and 29.1 ± 10.1 μmfor chicken, turkey, pheasant and bobwhite quail, respectively. In all four species, ketoconazole inhibited the production of both major metabolites of MDZ, with 4‐OH MDZ formation more sensitive to inhibition than 1‐OH MDZ. Pheasant and bobwhite quail appeared most sensitive to ketoconazole inhibition.
Pharmacodynamic effects and pharmacokinetic profile of a long‐term continuous rate infusion of racemic ketamine in healthy conscious horses
Authors: LANKVELD D. P. K. , DRIESSEN B. , SOMA L. R. , MOATE P. J. , RUDY J. , UBOH C. E. , VAN DIJK P. , HELLEBREKERS L. J.
Published: November 2006

Ketamine (KET) possesses analgesic and anti‐inflammatory activity at sub‐anesthetic doses, suggesting a benefit of long‐term KET treatment in horses suffering from pain, inflammatory tissue injury and/or endotoxemia. However, data describing the pharmacodynamic effects and safety of constant rate infusion (CRI) of KET and its pharmacokinetic profile in nonpremedicated horses are missing. Therefore, we administered to six healthy horses a CRI of 1.5 mg/kg/h KET over 320 min following initial drug loading. Cardiopulmonary parameters, arterial blood gases, glucose, lactate, cortisol, insulin, nonesterified fatty acids, and muscle enzyme levels were measured, as were plasma concentrations of KET and its metabolites using liquid chromatography‐tandem mass spectrometry (LC‐MS/MS). Levels of sedation and muscle tension were scored. Respiration and heart rate significantly increased during the early infusion phase. Glucose and cortisol significantly varied both during and after infusion. During CRI all horses scored 0 on sedation. All but one horse scored 0 on muscle tension, with one mare scoring 1. All other parameters remained within or close to physiological limits without significant changes from pre‐CRI values. The mean plasma concentration of KET during the 1.5 mg/kg/h KET CRI was 235 ng/mL. The decline of its plasma concentration–time curve of both KET and norketamine (NKET) following the CRI was described by a two‐compartmental model. The metabolic cascade of KET was NKET, hydroxynorketamine (HNK), and 5,6‐dehydronorketamine (DHNK). The KET median elimination half‐lives (t1/2αandt1/2β) were 2.3 and 67.4 min, respectively. The area under the KET plasma concentration–time curve (AUC), elimination was 76.0 μg·min/mL. Volumes of C1and C2were 0.24 and 0.79 L/kg, respectively. It was concluded that a KET CRI of 1.5 mg/kg/h can safely be administered to healthy conscious horses for at least 6 h, although a slight modification of the initial infusion rate regimen may be indicated. Furthermore, in the horse KET undergoes very rapid biotransformation to NKET and HNK and DHNK were the major terminal metabolites.
Pharmacokinetics of cefovecin in cats
Authors: STEGEMANN M. R. , SHERINGTON J. , COATI N. , BROWN S. A. , BLANCHFLOWER S.
Published: November 2006

The pharmacokinetics of the novel cephalosporin cefovecin were investigated in a series ofin vivo,ex vivoandin vitrostudies following administration to adult cats at 8 mg/kg bodyweight. Bioavailability and pharmacokinetic parameters were determined in a cross‐over study after intravenous (i.v.) and subcutaneous (s.c.) injections. [14C]cefovecin was used to evaluate excretion for 21 days after s.c. administration. Protein binding was determinedin vitroin feline plasma andex vivoin transudate from cats surgically implanted with tissue chambers. After s.c. administration, cefovecin was characterized by rapid absorption with mean peak plasma concentrations of 141 ± 12 μg/mL being achieved within 2 h of s.c. injection with full bioavailability (99%). The mean elimination half‐life was 166 ± 18 h. After i.v. administration, volume of distribution was 0.09 ± 0.01 L/kg and mean plasma clearance was 0.35 ± 0.04 mL/h/kg. Approximately 50% of the administered radiolabelled dose was eliminated over the 21‐day postdose period via urinary excretion and up to approximately 25% in faeces.In vitroandex vivoplasma protein binding ranged from 99.8% to 99.5% over the plasma concentration range 10–100 μg/mL.Ex vivoprotein binding in transudate was as low as 90.7%. From 8 h postdose, concentrations of unbound (free) cefovecin in transudate were consistently higher than in plasma, with mean unbound cefovecin concentrations being maintained above 0.06 μg/mL (MIC90ofPasteurella multocida) in transudate for at least 14 days postdose. The slow elimination and long‐lasting free concentrations in extracellular fluid are desirable pharmacokinetic attributes for an antimicrobial with a 14‐day dosing interval.
Effects of subcutaneous methadone, morphine, buprenorphine or saline on thermal and pressure thresholds in cats
Authors: STEAGALL P. V. M. , CARNICELLI P. , TAYLOR P. M. , LUNA S. P. L. , DIXON M. , FERREIRA T. H.
Published: November 2006

This study compared pressure and thermal thresholds after administration of three opioids in eight cats. Pressure stimulation was performed via a bracelet taped around the forearm. Three ball‐bearings were advanced against the forearm by inflation of a modified blood pressure bladder. Pressure in the cuff was recorded at the end point (leg shake and head turn). Thermal threshold was tested as previously reported using a heated probe held against the thorax [Dixon et al. (2002)Research in Veterinary Science, 72, 205]. After baseline recordings, each cat received subcutaneous methadone 0.2 mg/kg, morphine 0.2 mg/kg, buprenorphine 0.02 mg/kg or saline 0.3 mL in a four period cross‐over study. Measurements were made at 15, 30, 45 min and 1, 2, 3, 4, 8, 12 and 24 h after the injection. Data were analysed by anova (P < 0.05). There were no significant changes in thresholds after saline. Thermal threshold increased at 45 min after buprenorphine (maximum 2.8 ± 3 °C), 1–3 h after methadone (maximum 3.4 ± 1.9 °C) and 45 min to 1 h (maximum 3.4 ± 2 °C) after morphine. Pressure threshold increased 30–45 min (maximum 238 ± 206 mmHg) after buprenorphine, 45–60 min after methadone (maximum 255 ± 232 mmHg) and 45–60 min and 3–6 h (maximum 255 ± 232 mmHg) after morphine. Morphine provided the best analgesia, and methadone appears a promising alternative. Buprenorphines limited effect was probably related to the subcutaneous route of administration. Previously, buprenorphine has produced much greater effects when given by other routes.