bluuebunny/crossref_metadata_2025 huggingface dataset:
HIV-1 Vpu Blocks Recycling and Biosynthetic Transport of the Intrinsic Immunity Factor CD317/Tetherin To Overcome the Virion Release Restriction
Authors: Schmidt Sarah , Fritz Joëlle V. , Bitzegeio Julia , Fackler Oliver T. , Keppler Oliver T.
Published: May 2011

The intrinsic immunity factor CD317 (BST-2/HM1.24/tetherin) imposes a barrier to HIV-1 release at the cell surface that can be overcome by the viral protein Vpu. Expression of Vpu results in a reduction of CD317 surface levels; however, the mechanism of this Vpu activity and its contribution to the virological antagonism are incompletely understood. Here, we characterized the influence of Vpu on major CD317 trafficking pathways using quantitative antibody-based endocytosis and recycling assays as well as a microinjection/microscopy-based kinetic
de novo
expression approach. We report that HIV-1 Vpu inhibited both the anterograde transport of newly synthesized CD317 and the recycling of CD317 to the cell surface, while the kinetics of CD317 endocytosis remained unaffected. Vpu trapped trafficking CD317 molecules at the
trans
-Golgi network, where the two molecules colocalized. The subversion of both CD317 transport pathways was dependent on the highly conserved diserine S52/S56 motif of Vpu; however, it did not require recruitment of the diserine motif interactor and substrate adaptor of the SCF-E3 ubiquitin ligase complex, β-TrCP. Treatment of cells with the malaria drug primaquine resulted in a CD317 trafficking defect that mirrored that induced by Vpu. Importantly, primaquine could functionally replace Vpu as a CD317 antagonist and rescue HIV-1 particle release.

IMPORTANCE
HIV efficiently replicates in the human host and induces the life-threatening immunodeficiency AIDS. Mammalian genomes encode proteins such as CD317 that can inhibit viral replication at the cellular level. As a countermeasure, HIV has evolved genes like
vpu
that can antagonize these intrinsic immunity factors. Investigating the mechanism by which Vpu overcomes the virion release restriction imposed by CD317, we find that Vpu subverts recycling and anterograde trafficking pathways of CD317, resulting in surface levels of the restriction factor insufficient to block HIV-1 spread. This describes a novel mechanism of immune evasion by HIV.
Transient Suppression of Shigella flexneri Type 3 Secretion by a Protective O-Antigen-Specific Monoclonal IgA
Authors: Forbes Stephen J. , Bumpus Tia , McCarthy Elizabeth A. , Corthésy Blaise , Mantis Nicholas J.
Published: May 2011

Mucosal immunity to the enteric pathogen
Shigella flexneri
is mediated by secretory IgA (S-IgA) antibodies directed against the O-antigen (O-Ag) side chain of lipopolysaccharide. While secretory antibodies against the O-Ag are known to prevent bacterial invasion of the intestinal epithelium, the mechanisms by which this occurs are not fully understood. In this study, we report that the binding of a murine monoclonal IgA (IgAC5) to the O-Ag of
S. flexneri
serotype 5a suppresses activity of the type 3 secretion (T3S) system, which is necessary for
S. flexneri
to gain entry into intestinal epithelial cells. IgAC5’s effects on the T3S were rapid (5 to 15 min) and were coincident with a partial reduction in the bacterial membrane potential and a decrease in intracellular ATP levels. Activity of the T3S system returned to normal levels 45 to 90 min following antibody treatment, demonstrating that IgAC5’s effects were transient. Nonetheless, these data suggest a model in which the association of IgA with the O-Ag of
S. flexneri
partially de-energizes the T3S system and temporarily renders the bacterium incapable of invading intestinal epithelial cells.

IMPORTANCE
Secretory IgA (S-IgA) serves as the first line of defense against enteric infections. However, despite its well-recognized role in mucosal immunity, relatively little is known at the molecular level about how this class of antibody functions to prevent pathogenic bacteria from penetrating the epithelial barrier. It is generally assumed that S-IgA functions primarily by “immune exclusion,” a phenomenon in which the antibody binds to microbial surface antigens and thereby promotes bacterial agglutination, entrapment in mucus, and physical clearance from the gastrointestinal tract via peristalsis. The results of the present study suggest that in addition to serving as a physical barrier, S-IgA may have a direct impact on the ability of microbial pathogens to secrete virulence factors required for invasion of intestinal epithelial cells.
Streptococcus pneumoniae Is Desiccation Tolerant and Infectious upon Rehydration
Authors: Walsh Rebecca L. , Camilli Andrew
Published: May 2011

Streptococcus pneumoniae
(pneumococcus) is a frequent colonizer of the nasopharynx and one of the leading causative agents of otitis media, pneumonia, and meningitis. The current literature asserts that
S. pneumoniae
is transmitted person to person via respiratory droplets; however, environmental surfaces (fomites) have been linked to the spread of other respiratory pathogens. Desiccation tolerance has been to shown to be essential for long-term survival on dry surfaces. This study investigated the survival and infectivity of
S. pneumoniae
following desiccation under ambient conditions. We recovered viable bacteria after all desiccation periods tested, ranging from 1 h to 4 weeks. Experiments conducted under nutrient limitation indicate that desiccation is a condition separate from starvation. Desiccation of an acapsular mutant and 15 different clinical isolates shows that
S. pneumoniae
desiccation tolerance is independent of the polysaccharide capsule and is a species-wide phenomenon, respectively. Experiments demonstrating that nondesiccated and desiccated
S. pneumoniae
strains colonize the nasopharynx at comparable levels, combined with their ability to survive long-term desiccation, suggest that fomites may serve as alternate sources of pneumococcal infection.

IMPORTANCE
Even with the advent of multivalent capsular polysaccharide conjugate vaccines,
S. pneumoniae
continues to be a major cause of morbidity and mortality worldwide. Every year, there are approximately 7 million cases of pneumococcus-based otitis media in the United States alone, while pneumococcal invasive diseases are responsible for more than 1 million deaths globally. It is believed that the human upper respiratory tract is the sole niche of
S. pneumoniae
and, thus, that spread occurs via close contact with an infected individual. In this study, we characterized the desiccation tolerance of
S. pneumoniae
and found that it can survive for many weeks postdehydration and retain infectivity. Our results suggest that desiccation tolerance is an inherent trait of this genetically variable species and that fomites may be a source of transmission.
A rich Ediacaran assemblage from eastern Avalonia: Evidence of early widespread diversity in the deep ocean
Authors: Wilby Philip R. , Carney John N. , Howe Michael P.A.
Published: May 2011

The Avalon Assemblage (Ediacaran, late Neoproterozoic) provides some of the oldest evidence of diverse macroscopic life and underpins current understanding of the early evolution of epibenthic communities. However, its overall diversity and provincial variability are poorly constrained and are based largely on biotas preserved in Newfoundland, Canada. We report coeval high-diversity biotas from Charnwood Forest, UK, which share at least 60% of their genera in common with ones in Newfoundland. This indicates that substantial taxonomic exchange took place between different regions of Avalonia, probably facilitated by ocean currents, and suggests that a diverse deepwater biota may already have been widespread at the time. Contrasts in the relative abundance of prostrate versus erect taxa likely record differential sensitivity to physical environmental parameters (hydrodynamic regime, substrate) and highlight their significance in controlling community structure.
Dunites from Isua, Greenland: A ca. 3720 Ma window into subcrustal metasomatism of depleted mantle
Authors: Friend C.R.L. , Nutman A.P.
Published: May 2011

The chemistry of surviving pieces of Eoarchaean mantle together with related crust helps us determine early crust-forming mechanisms. Two lenses of high-Mg, low-Al dunite within a ca. 3720 Ma part of the Isua supracrustal belt in Greenland are interpreted as relicts of Eoarchaean mantle with minimal crustal disturbance. The lenses are within altered, higher Al, Ca ultramafic schists and are intercalated with amphibolitized pillow basalts and gabbros with island arc chemical signatures, all intruded by 3715–3710 Ma tonalites. One variety of dunite is dominated by forsterite (Fo90–92) olivine with accessory chromite and rare clinopyroxene, which does not show high field strength element (HFSE) anomalies. Another variety contains olivine (Fo96–98), some intergrown with Ti-humite group minerals with strong positive HFSE anomalies that are complementary to the negative HFSE anomalies of the adjacent amphibolites. We propose that these dunites are tectonic slivers of ca. 3720 Ma subarc mantle that preserve evidence for varying interaction with mafic magmas in a ≥850 °C, 1.7–2.0 GPa subcrustal environment. These are by far the oldest direct geochemical link between coeval mantle and crustal rocks, and are new evidence for subduction zone–like environments on the early Earth.
Taphonomic study of Ediacaran organic-walled fossils confirms the importance of clay minerals and pyrite in Burgess Shale−type preservation
Authors: Anderson Evan P. , Schiffbauer James D. , Xiao Shuhai
Published: May 2011

Burgess Shale−type (BST) macrofossils and organic-walled microfossils are preserved as carbonaceous compressions and may share similar taphonomic processes. Previous taphonomic investigations of carbonaceous compressions have primarily focused on the microchemistry of Cambrian BST fossils, but comparative data from organic-walled microfossils were not available. To address these issues, we analyzed two organic-walled taxa from the Yangtze Gorges area of the South China block, Chuaria (an acritarch) and Vendotaenia (a ribbon-shaped fossil). Their abundance offers the opportunity for destructive microanalysis, including petrography, electron microscopy, and elemental mapping on both bedding planes and in cross sections. Our data suggest that Chuaria preservation is remarkably similar to BST fossils in that its vesicle walls are closely associated with clay minerals. In addition, like many BST macrofossils, Chuaria and Vendotaenia are also closely associated with pyrite; Chuaria vesicles are often filled with framboidal pyrite, and Vendotaenia fossils are associated with sulfate, partly derived from pyrite oxidation. The comparative taphonomy of Chuaria and Vendotaenia and BST macrofossils indicates that the preservation of organic-walled acritarchs may be aided by clay and pyrite mineralization, and that these abundant microfossils may serve as proxies for uncovering in more detail the taphonomic histories of BST preservation.
Reconciling geologic and geodetic model fault slip-rate discrepancies in Southern California: Consideration of nonsteady mantle flow and lower crustal fault creep
Authors: Chuang Ray Y. , Johnson Kaj M.
Published: May 2011

In Southern California, slip rates derived from geodesy-constrained elastic models are lower than geologic rates along the Mojave and San Bernardino segments of the San Andreas fault and the Garlock fault. In contrast, the summed geodetic rate across the Mojave eastern California shear zone (ECSZ) is significantly higher than the summed geologic rate. We show that geodetic and geologic slip rates in Southern California can be reconciled using a viscoelastic earthquake cycle model that explicitly incorporates time-dependent deformation due to nonsteady interseismic fault creep in the lower crust and viscous flow in the upper mantle. To reconcile geologic and geodetic model rates, our model requires that the southern San Andreas fault and the Garlock fault are in the late stages of the earthquake cycle, resulting in lower current deformation rates than the cycle-averaged rate. Our model implies that the ECSZ and the San Jacinto faults are in the early stages of the earthquake cycle, resulting in high current deformation rates.
Crustal emplacement of exhuming (ultra)high-pressure rocks: Will that be pro- or retro-side?
Authors: Butler J.P. , Beaumont C. , Jamieson R.A.
Published: May 2011

(Ultra)high-pressure [(U)HP] rocks form and exhume from deep within subduction channels, but subsequent horizontal transport in the shallower orogenic crust makes it difficult to reconstruct their tectonic histories. We use a conceptual framework and numerical models to show that buoyant exhumation from within a subduction conduit formed during one-sided subduction may lead to emplacement of (U)HP rocks into either the lower plate (prowedge) or upper plate (retrowedge) of an orogen, depending on whether the upper plate crust deforms or acts as a backstop during exhumation. Both modes may operate at different positions or different times within an orogen, leading to emplacement of (U)HP rocks into both plates without changing subduction geometry. We propose that retrotransport during exhumation may explain some (U)HP rocks (e.g., Liverpool Land) situated in the upper plate of the Greenland-Norwegian Caledonides.
Associations between cigarette smoking, obesity, sociodemographic characteristics and remote-sensing-derived estimates of ambient PM2.5: results from a Canadian population-based survey
Authors: Villeneuve Paul J , Goldberg Mark S , Burnett Richard T , van Donkelaar Aaron , Chen Hong , Martin Randall V
Published: May 2011

Objectives

Long-term exposure to ambient fine particles (PM2.5) has been shown to increase mortality. Variables measured on the same spatial scales of air pollution may confound associations, and so the authors' objectives were to evaluate the associations between PM2.5and individual-level measures of smoking, obesity and sociodemographic status. The authors present an approach to evaluate the impact that uncontrolled confounding from smoking may have on associations between PM2.5and mortality.

Methods

Individual-level behavioural and sociodemographic data were obtained from a 2003 national survey of 122 548 Canadians. Estimates of ground-level PM2.5at a resolution of 10×10 km between 2001 and 2006 were derived from satellite remote sensing. Exposures were assigned to the residence of the participants at the time of the survey. Differences in the prevalence of smoking across concentrations of PM2.5and RRs drawn from the literature were used to model the bias on rate ratios.

Results

Participants in areas with higher concentrations of PM2.5had a higher income and educational attainment, smoked less and were more likely immigrants. Smoking had a negative confounding effect on the associations between PM2.5and mortality. To compensate for this bias, for a 10 μg/m3increase in PM2.5, mortality from lung cancer and heart disease in the referent exposure group needed to be increased by 6.9% and 3.2%, respectively.

Conclusions

Associations were found between sociodemographic and lifestyle characteristics and PM2.5at a resolution of 10×10 km. The authors present a model to adjust for uncontrolled confounding of smoking that can be readily adapted to exposures measured at different spatial resolutions.
PARITY OF CHARGED PIONS
Authors: ROBSON B. A.
Published: May 2011

This paper discusses the parity of charged pions. It is shown that the original determination of the parity of the negatively charged pion using the capture of negatively charged pions in deuterium to form two neutrons is not conclusive if the pion has a complex substructure. It is demonstrated that this experiment is compatible with the mixed-parity nature of the π- arising in a recent composite model. A major consequence of this is that CP may be conserved in the [Formula: see text] system.
DISCUSSION OF QUANTUM INVERSE SCATTERING PROBLEMS FOR COUPLED CHANNELS AT FIXED ENERGY
Authors: SCHEID WERNER , APAGYI BARNABAS
Published: May 2011

In nuclear physics, the inverse scattering problem for coupled channels at fixed energies searches for the coupling potentials by using the S matrix as information. On the basis of the Newton–Sabatier method we investigate the special case that the coupling is independent of the total angular momentum. We discuss transparent potentials and consider a principal, but not practical method for the solution of coupling potentials dependent on total angular momentum.
SOLITON STEERING IN A RAMP WAVEGUIDE WITH NONLOCAL NONLINEARITY
Authors: SURYANTO A. , DARTI I.
Published: May 2011

We present an analytical and numerical investigation of a spatial soliton propagating in a waveguide with ramp linear refractive index profile (ramp waveguide) and nonlocal nonlinearity. It is shown analytically by equivalent particle approach and numerically by implicit Crank-Nicolson scheme that in a ramp waveguide with local nonlinearity, the soliton experiences negative acceleration along the waveguide where its refractive index decreases linearly. On the other hand, if the soliton propagates in a uniform medium with nonlocal nonlinear response then it will experience a self-bending in the positive direction where the bending level depends on the soliton amplitude as well as on the strength of nonlocality. By combining these two effects, rich dynamics of soliton can be achieved. In this case, the soliton may oscillate inside the waveguide, move to the left or to the right part of the waveguide or even be trapped. Such soliton steering can be controlled by the soliton amplitude or by its initial position.
Insulin regulates its own delivery to skeletal muscle by feed-forward actions on the vasculature
Authors: Barrett Eugene J. , Wang Hong , Upchurch Charles T. , Liu Zhenqi
Published: May 2011

Insulin, at physiological concentrations, regulates the volume of microvasculature perfused within skeletal and cardiac muscle. It can also, by relaxing the larger resistance vessels, increase total muscle blood flow. Both of these effects require endothelial cell nitric oxide generation and smooth muscle cell relaxation, and each could increase delivery of insulin and nutrients to muscle. The capillary microvasculature possesses the greatest endothelial surface area of the body. Yet, whether insulin acts on the capillary endothelial cell is not known. Here, we review insulin's actions at each of three levels of the arterial vasculature as well as recent data suggesting that insulin can regulate a vesicular transport system within the endothelial cell. This latter action, if it occurs at the capillary level, could enhance insulin delivery to muscle interstitium and thereby complement insulin's actions on arteriolar endothelium to increase insulin delivery. We also review work that suggests that this action of insulin on vesicle transport depends on endothelial cell nitric oxide generation and that insulin's ability to regulate this vesicular transport system is impaired by inflammatory cytokines that provoke insulin resistance.
Click-evoked responses in vestibular afferents in rats
Authors: Zhu Hong , Tang Xuehui , Wei Wei , Mustain William , Xu Youguo , Zhou Wu
Published: May 2011

Sound activates not only the cochlea but also the vestibular end organs. Research on this phenomenon led to the discovery of the sound-evoked vestibular myogenic potentials recorded from the sternocleidomastoid muscles (cervical VEMP, or cVEMP). Since the cVEMP offers simplicity and the ability to stimulate each labyrinth separately, its values as a test of human vestibular function are widely recognized. Currently, the cVEMP is interpreted as a test of saccule function based on the assumption that clicks primarily activate the saccule. However, sound activation of vestibular end organs other than the saccule has been reported. To provide the neural basis for interpreting clinical VEMP testing, we employed the broadband clicks used in clinical VEMP testing to examine the sound-evoked responses in a large sample of vestibular afferents in Sprague-Dawley rats. Recordings were made from 924 vestibular afferents from 106 rats: 255 from the anterior canal (AC), 202 from the horizontal canal (HC), 177 from the posterior canal (PC), 207 from the superior vestibular nerve otolith (SO), and 83 from the inferior nerve otolith (IO). Sound sensitivity of each afferent was quantified by computing the cumulative probability of evoking a spike (CPE). We found that clicks activated irregular afferents (normalized coefficient of variation of interspike intervals >0.2) from both the otoliths (81%) and the canals (43%). The order of end organ sound sensitivity was SO = IO > AC > HC > PC. Since the sternocleidomastoid motoneurons receive inputs from both the otoliths and the canals, these results provide evidence of a possible contribution from both of them to the click-evoked cVEMP.
Three-dimensional localization of neurons in cortical tetrode recordings
Authors: Mechler Ferenc , Victor Jonathan D. , Ohiorhenuan Ifije , Schmid Anita M. , Hu Qin
Published: May 2011

The recording radius and spatial selectivity of an extracellular probe are important for interpreting neurophysiological recordings but are rarely measured. Moreover, an analysis of the recording biophysics of multisite probes (e.g., tetrodes) can provide for source characterization and localization of spiking single units, but this capability has remained largely unexploited. Here we address both issues quantitatively. Advancing a tetrode (≈40-μm contact separation, tetrahedral geometry) in 5- to 10-μm steps, we repeatedly recorded extracellular action potentials (EAPs) of single neurons in the visual cortex. Using measured spatial variation of EAPs, the tetrodes' measured geometry, and a volume conductor model of the cortical tissue, we solved the inverse problem of estimating the location and the size of the equivalent dipole model of the spike generator associated with each neuron. Half of the 61 visual neurons were localized within a radius of ≈100 μm and 95% within ≈130 μm around the tetrode tip (i.e., a large fraction was much further than previously thought). Because of the combined angular sensitivity of the tetrode's leads, location uncertainty was less than one-half the cell's distance. We quantified the spatial dependence of the probability of cell isolation, the isolated fraction, and the dependence of the recording radius on probe size and equivalent dipole size. We also reconstructed the spatial configuration of sets of simultaneously recorded neurons to demonstrate the potential use of 3D dipole localization for functional anatomy. Finally, we found that the dipole moment vector, surprisingly, tended to point toward the probe, leading to the interpretation that the equivalent dipole represents a “local lobe” of the dendritic arbor.
Receptive field center size decreases and firing properties mature in ON and OFF retinal ganglion cells after eye opening in the mouse
Authors: Koehler Christopher L. , Akimov Nikolay P. , Rentería René C.
Published: May 2011

Development of the mammalian visual system is not complete at birth but continues postnatally well after eye opening. Although numerous studies have revealed changes in the development of the thalamus and visual cortex during this time, less is known about the development of response properties of retinal ganglion cells (RGCs). Here, we mapped functional receptive fields of mouse RGCs using a Gaussian white noise checkerboard stimulus and a multielectrode array to record from retinas at eye opening, 3 days later, and 4 wk after birth, when visual responses are essentially mature. Over this time, the receptive field center size of ON and OFF RGC populations decreased. The average receptive field center size of ON RGCs was larger than that of OFF RGCs at eye opening, but they decreased to the same size in the adult. Firing properties were also immature at eye opening. RGCs had longer latencies, lower frequencies of firing, and lower sensitivity than in the adult. Hence, the dramatic maturation of the visual system during the first weeks of visual experience includes the retina.
A New Fuzzy Clustering Algorithm Based on Clonal Selection for Land Cover Classification
Authors: Zhong Yanfei , Zhang Liangpei
Published: May 2011

A new fuzzy clustering algorithm based on clonal selection theory from artificial immune systems (AIS), namely, FCSA, is proposed to obtain the optimal clustering result of land cover classification without a priori assumptions on the number of clusters. FCSA can adaptively find the optimal number of clusters and is designed as a two‐layer system: the classification layer and the optimization layer. The classification layer of FCSA, inspired by clonal selection theory, generates the optimal classification result with a fixed cluster number by utilizing the clone, mutation, and selection of immune operators. The optimization layer of FCSA evaluates the optimal solutions according to performance measures for cluster validity and then adjusts the cluster number to output the final optimal cluster number. Two experiments with different types of image evince that FCSA not only finds the optimal number of clusters, but also consistently outperforms the traditional clustering algorithms, such as K‐means and Fuzzy C‐means. Hence, FCSA provides an effective option for performing the task of land cover classification.
Efficacy and Tolerability of a Combined Moxifloxacin/Dexamethasone Formulation for Topical Prophylaxis in Phacoemulsification: An Open-Label Single-Arm Clinical Trial
Authors: Espiritu Cesar Ramon G. , Sy Mary Ellen A. , Tayengco Tommee Lynne G.
Published: May 2011

Background. The use of a fixed-combination antibiotic corticosteroid for infection prophylaxis in Asian patients undergoing phacoemulsification has not been reported.Methods. A 15-day, open-label, single-arm trial of 64 patients for phacoemulsification with intraocular lens (IOL) implantation is described. Patients applied moxifloxacin 0.5%/dexamethasone 0.1% (Vigadexa) eye drops four times daily before and until 15 days after surgery. Anterior chamber (AC) reaction, visual acuity, ocular pain and signs, and intraocular pressure (IOP) were assessed at baseline and on postoperative days 1, 3, 8, and 15.Results. At day 15, 55 (91.7%) patients scored 0 (<5 cells) in AC reaction. No surgery-related infection occurred. Mean best-corrected visual acuity improved 0.5 logMAR from baseline to 0.0 logMAR (P<.0001). Mean IOP remained at 12-13 mm Hg over the 15-day treatment. Only 2 patients (3.1%) reported minimum ocular pain. Two (3.1%) patients were shifted to prednisolone acetate for severe inflammation. At the end of the study period, 8.3% were given fluorometholone for 1 week for AC reaction grade >0. No drug-related adverse event was reported.Conclusion. Following phacoemulsification and IOL implantation, the topical combination moxifloxacin 0.5%/dexamethasone 0.1% was effective in preventing infection and controlling inflammation and was well tolerated.
Synchronization for an Array of Coupled Cohen‐Grossberg Neural Networks with Time‐Varying Delay
Authors: Zhang Haitao , Li Tao , Fei Shumin
Published: May 2011

This paper makes some great attempts to investigate the global exponential synchronization
for arrays of coupled delayed Cohen‐Grossberg neural networks with both delayed coupling and one single
delayed one. By resorting to free‐weighting matrix and Kronecker product techniques, two novel synchronization criteria via linear matrix inequalities (LMIs) are presented based on convex combination, in
which these conditions are heavily dependent on the bounds of both the delay and its derivative. Owing
to that the addressed system can include some famous neural network models as the special cases, the
proposed methods can extend and improve those earlier reported ones. The efficiency and applicability
of the presented conditions can be demonstrated by two numerical examples with simulations.
Allometry and Interspecific Differences in the Facial Cranium of Two Closely Related Macaque Species
Authors: Ito Tsuyoshi , Nishimura Takeshi , Takai Masanaru
Published: May 2011

Interpreting evolutionary history of macaque monkeys from fossil evidence is difficult, because their evolutionary fluctuations in body size might have removed or formed important morphological features differently in each lineage. We employed geometric morphometrics to explore allometric trajectories of craniofacial shape in two closely related species, Macaca fascicularis and M. fuscata. These two species exhibit a single shared allometric trajectory in superoinferior deflection of the anterior face, indicating that the differences in this feature can be explained by size variation. In contrast, two parallel trajectories are demonstrated in craniofacial protrusion, indicating that even if they are comparable in size, M. fuscata has a higher and shorter face than M. fascicularis. The degree of facial protrusion is most likely a critical feature for phyletic evaluation in the fascicularis group. Such analyses in various macaques would help to resolve controversies regarding phyletic interpretations of fossil macaques.
Relationships between Brain Structure and Metabolic Changes in Schizophrenia Patients Treated with Olanzapine: A Voxel-Based Morphometric Study
Authors: Letourneau Genevieve , Bentaleb Lahcen Ait , Stip Benjamin , Luck David , Stip Emmanuel
Published: May 2011

Introduction. Second-generation antipsychotics treatment is associated with weight gain and metabolic disturbances. Although much research has been done on the topic, the precise mechanisms underlying such side effects are still not well understood.Method. We followed over 16 weeks a group of 17 schizophrenia patients who were treated with olanzapine and monitored biometric, clinical, and metabolic data, including ghrelin and leptin levels. All patients had a structural cerebral magnetic resonance imaging examination during the first week of their followup and at the end of the study.Results. We found positive and negative significant correlations between grey matter volumes of several brain regions and variations of body weight as well as of ghrelin and leptin levels. The right frontal operculum, bilateral precuneus, and bilateral hippocampal regions were found to be significantly associated with those changes.Conclusion. Our results suggest associations between brain structure and metabolic variations in schizophrenia patients taking olanzapine.
Efficient Boundary Extraction from Orthogonal Pseudo‐Polytopes: An Approach Based on the nD‐EVM
Authors: Pérez-Aguila Ricardo
Published: May 2011

This work is devoted to contribute with two algorithms for performing, in an efficient way, connected components labeling and boundary extraction from orthogonal pseudo‐polytopes. The proposals are specified in terms of the extreme vertices model in the n‐dimensional space (nD‐EVM). An overview of the model is presented, considering aspects such as its fundamentals and basic algorithms. The temporal efficiency of the two proposed algorithms is sustained in empirical way and by taking into account both lower dimensional cases (2D and 3D) and higher‐dimensional cases (4D and 5D).
Genome-Wide Analysis of Promoter Methylation Associated with Gene Expression Profile in Pancreatic Adenocarcinoma
Authors: Vincent Audrey , Omura Noriyuki , Hong Seung-Mo , Jaffe Andrew , Eshleman James , Goggins Michael
Published: May 2011

Purpose: The goal of this study was to comprehensively identify CpG island methylation alterations between pancreatic cancers and normal pancreata and their associated gene expression alterations.

Experimental Design: We employed methylated CpG island amplification followed by CpG island microarray, a method previously validated for its accuracy and reproducibility, to analyze the methylation profile of 27,800 CpG islands covering 21 MB of the human genome in nine pairs of pancreatic cancer versus normal pancreatic epithelial tissues and in three matched pairs of pancreatic cancer versus lymphoid tissues from the same individual.

Results: This analysis identified 1,658 known loci that were commonly differentially methylated in pancreatic cancer compared with normal pancreas. By integrating the pancreatic DNA methylation status with the gene expression profiles of the same samples before and after treatment with the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine, and the histone deacetylase inhibitor, trichostatin A, we identified dozens of aberrantly methylated and differentially expressed genes in pancreatic cancers including a more comprehensive list of hypermethylated and silenced genes that have not been previously described as targets for aberrant methylation in cancer.

Conclusion: We expected that the identification of aberrantly hypermethylated and silenced genes will have diagnostic, prognostic, and therapeutic applications. Clin Cancer Res; 17(13); 4341–54. ©2011 AACR.
Distinct Apoptotic Signaling Characteristics of the Anti-CD40 Monoclonal Antibody Dacetuzumab and Rituximab Produce Enhanced Antitumor Activity in Non-Hodgkin Lymphoma
Authors: Lewis Timothy S. , McCormick Renee S. , Emmerton Kim , Lau Jeffrey T. , Yu Shang-Fan , McEarchern Julie A. , Grewal Iqbal S. , Law Che-Leung
Published: May 2011

Purpose: Individually targeting B-cell antigens with monoclonal antibody therapeutics has improved the treatment of non-Hodgkin lymphoma (NHL). We examined if the antitumor activity of rituximab, CD20-specific antibody, could be improved by simultaneously targeting CD40 with the humanized monoclonal antibody dacetuzumab (SGN-40).

Experimental Design: Dacetuzumab was dosed with rituximab to determine the in vivo activity of this combination in a subcutaneous Ramos xenograft model of non-Hodgkin lymphoma (NHL). The effect of dacetuzumab on rituximab antibody-dependent cell mediated–cytotoxicity (ADCC), antiproliferative, and apoptotic activities were evaluated in vitro using NHL cell lines. Western blotting and flow cytometry were used to contrast the signaling pathways activated by dacetuzumab and rituximab in NHL cells.

Results: The dacetuzumab-rituximab combination had significantly improved antitumor activity over the equivalent dose of rituximab in the Ramos xenograft model (P = 0.0021). Dacetuzumab did not augment rituximab-mediated ADCC activity; however, these antibodies were additive to synergistic in cell-proliferation assays and produced increased apoptosis in combination. Rituximab signaling downregulated BCL-6 oncoprotein in a cell line–specific manner, whereas dacetuzumab strongly downregulated BCL-6 in each cell line. Dacetuzumab induced expression of the proapoptotic proteins TAp63 and Fas, whereas rituximab did not affect basal expression of either protein. Finally, rituximab partially blocked dacetuzumab-mediated upregulation of the prosurvival protein BCL-xL.

Conclusions: Targeting CD40 with dacetuzumab enhanced the antitumor activity of rituximab in cell line and xenograft NHL models. The distinct but complementary apoptotic signal transduction profiles of dacetuzumab and rituximab are an important mechanism behind the improved activity of this combination. Clin Cancer Res; 17(14); 4672–81. ©2011 AACR.
Pharmacokinetic–Pharmacodynamic Analysis of Vismodegib in Preclinical Models of Mutational and Ligand-Dependent Hedgehog Pathway Activation
Authors: Wong Harvey , Alicke Bruno , West Kristina A. , Pacheco Patricia , La Hank , Januario Tom , Yauch Robert L. , de Sauvage Frederic J. , Gould Stephen E.
Published: May 2011

Purpose: Vismodegib (GDC-0449) is a potent and selective inhibitor of the Hedgehog (Hh) pathway that shows antitumor activity in preclinical models driven by mutational or ligand-dependent activation of the Hh pathway. We wished to characterize the pharmacokinetic–pharmacodynamic (PK/PD) relationship of vismodegib in both model systems to guide optimal dose and schedule for vismodegib in the clinic.

Experimental Design: Preclinical efficacy and PK/PD studies were carried out with vismodegib in a Ptch+/− allograft model of medulloblastoma exhibiting mutational activation of the Hh pathway and patient-derived colorectal cancer (CRC) xenograft models exhibiting ligand-dependent pathway activation. Inhibition of the hedgehog pathway was related to vismodegib levels in plasma and to antitumor efficacy using an integrated population-based PK/PD model.

Results: Oral dosing of vismodegib caused tumor regressions in the Ptch+/− allograft model of medulloblastoma at doses ≥25 mg/kg and tumor growth inhibition at doses up to 92 mg/kg dosed twice daily in two ligand-dependent CRC models, D5123, and 1040830. Analysis of Hh pathway activity and PK/PD modeling reveals that vismodegib inhibits Gli1 with a similar IC50 in both the medulloblastoma and D5123 models (0.165 μmol/L ±11.5% and 0.267 μmol/L ±4.83%, respectively). Pathway modulation was linked to efficacy using an integrated PK/PD model revealing a steep relationship where > 50% of the activity of vismodegib is associated with >80% repression of the Hh pathway.

Conclusions: These results suggest that even small reductions in vismodegib exposure can lead to large changes in antitumor activity and will help guide proper dose selection for vismodegib in the clinic. Clin Cancer Res; 17(14); 4682–92. ©2011 AACR.
Developmental Expression and Distribution of GABAA Receptor α1-, α3- and β2-Subunits in Pig Brain
Authors: Kalanjati Viskasari P. , Miller Stephanie M. , Ireland Zoe , Colditz Paul B. , Bjorkman Stella T.
Published: May 2011

The principal function of the γ-aminobutyric acid (GABA) system in the adult brain is inhibition; however, in the neonatal brain, GABA provides much of the excitatory drive. As the brain develops, transmembrane chloride gradients change and the inhibitory role of GABA is initiated and continues throughout juvenile and adult life. Previous studies have shown that GABAA receptor subunit expression is developmentally regulated, and it is thought that the change in GABA function from excitation to inhibition corresponds to the changeover in expression of ‘immature’ to ‘mature’ subunit isoforms. We examined the protein expression pattern and distribution of GABA type A (GABAA) receptor α1-, α3- and β2-subunits in the parietal cortex and hippocampus of the developing piglet brain. Four perinatal ages were studied; 14 days preterm (P–14), 10 days preterm (P–10), day of birth (P0) and at postnatal day 7 (P7). Animals were obtained by either caesarean section or spontaneous birth. Protein expression levels and subunit localization were analysed by Western blotting and immunohistochemistry, respectively. In the cortex and hippocampus, GABAA receptor α1-subunit showed greatest expression at P7 when compared to all other age groups (p < 0.05). In contrast, α3 expression in the cortex was elevated in preterm brain, peaking at P0, followed by a significant reduction by P7 (p < 0.05); a similar trend was observed in the hippocampus. GABAA receptor β2-subunit protein expression appeared relatively constant across all time points studied in both the cortex and hippocampus. Immunolabelling of the α1-, α3- and β2-subunits was observed throughout all cortical layers at every age. GABAA receptor α3-subunit appeared to show specific localization to layers V and VI whilst labelling for the β2-subunit was observed in layer IV. In the hippocampus of all animals, the α1- and β2-subunits were shown to immunolabel various cells and processes in the dentate gyrus (DG), CA1 and CA3; the α3-subunit was barely observed except at the stratum moleculare of the DG. We report for the first time the ontogenesis of GABAA receptor subunits α1, α3 and β2 in the perinatal pig brain.
Trigeminal Neuralgia Associated with the Specific Bridging Pattern of Transverse Pontine Vein: Diagnostic Value of Three-Dimensional Multifusion Volumetric Imaging
Authors: Oishi Makoto , Fukuda Masafumi , Noto Yoshiyuki , Kawaguchi Tadashi , Hiraishi Tetsuya , Fujii Yukihiko
Published: May 2011

Objectives: We report the specific bridging pattern of a transverse pontine vein (TPV) associated with trigeminal neuralgia (TN), which was evaluated by 3-dimensional (3D) multifusion volumetric imaging (MFVI). Methods: In 3 cases with TN (V1 or V1–2 territory), constructive interference in steady state (CISS) imaging confirmed no arterial compression but indicated a vein draining into Meckel’s cave. Virtual endoscopic (VE) analysis for CISS images and 3D MFVI (in 2 cases) including venous information was obtained by a multidetector row computed tomography (MDCT) system. Additionally, we investigated the bridging pattern of veins around Meckel’s cave on 3D MFVI of 50 cerebellopontine angle (CPA) regions without any lesions. Results: In all 3 patients, VE of CISS or 3D MFVI identified a bridging vein from the TPV causing the focal deformity of the trigeminal nerve near Meckel’s cave. All those patients achieved a pain-free state after surgically coagulating and cutting the vein. In investigating 3D MFVI of 50 CPA regions, this type of the bridging vein was found in 4 (8%) including the presented 2 cases. Conclusions: The specific bridging pattern of the TPV draining into Meckel’s cave can be associated with TN. The 3D MFVI analysis using venous information obtained by MDCT was useful to evaluate surgical anatomy including the offending vein which can be missed.
Effects of Dialysate Glucose Concentration on Heart Rate Variability in Chronic Hemodialysis Patients: Results of a Prospective Randomized Trial
Authors: Ferrario Manuela , Raimann Jochen G. , Thijssen Stephan , Signorini Maria Gabriella , Kruse Anja , Diaz-Buxo Jose A. , Cerutti Sergio , Levin Nathan W. , Kotanko Peter
Published: May 2011

Background: Chronic hemodialysis (HD) patients suffer from an appallingly high cardiovascular mortality. During HD, patients are exposed to dialysate glucose, which may alter blood glucose levels and thus exert effects on the autonomic nervous system. Heart rate variability (HRV) is an established indicator of autonomic nervous system activity and a predictor of cardiovascular outcomes. This study investigated the effects of two commonly used dialysate glucose concentrations [100 mg/dl (HD100), and 200 mg/dl (HD200)] on HRV in chronic HD patients. Methods: In this prospective, randomized, controlled, single-masked, cross-over trial, subjects were randomized to receive HD100 or HD200 for a period of 3 weeks followed by a cross-over to the respective other dialysate (www.clinicaltrials.gov #NCT00618033). Blood glucose and insulin levels were measured before and after HD. Intradialytic Holter electrocardiograms were recorded and HRV time domain, frequency domain and complexity parameters analyzed. Results: Twenty-three HD patients (age 56 ± 12 years, 11 male, 14 black, 11 with diabetes) were studied. Diabetic subjects showed significantly higher serum glucose levels with HD200 as compared to HD100 (HD100: 146 ± 48 mg/dl; HD200: 192 ± 57 mg/dl; p < 0.01); this hyperglycemia was accompanied by an increase of the high-frequency band of HRV (p = 0.019), a reflection of increased parasympathetic activity. HRV did not change in nondiabetic subjects. Conclusion: In diabetic subjects, the use of HD200 increased vagal tone. Given the importance of sympathetic activation to counteract intradialytic hypotension, our findings support the use of HD100 in diabetic HD patients.
Weight Change, Blood Pressure, Lipids and Glycemic Control among Patients with Type 2 Diabetes
Authors: Janghorbani Mohsen , Amini Masoud , Salehi-Marzijarani Mohammad
Published: May 2011

Background/Aim: Although weight loss in patients with type 2 diabetes is very important, available data on the effects of long-term weight change on blood pressure (BP), lipids and glycemic control in these patients are limited. The aim of this study was to assess the long-term impact of weight change on BP, plasma lipids and glycemic control among patients with type 2 diabetes receiving routine care. Methods: During the mean [standard deviation (SD)] follow-up period of 9.2 (3.4; range 2–15) years, 7,712 patients with type 2 diabetes were examined to determine changes in weight, BP, plasma lipids and glycemic control using a linear mixed-effects model for repeated measures. The mean (SD) age of participants was 51.3 (10.5) years with a mean (SD) duration of diabetes of 6.3 (6.3) years at initial registration. Results: The change in fasting plasma glucose and glycosylated hemoglobin (HbA1c) from baseline to the last follow-up examination was significantly more favorable in those patients who gained weight during follow-up than in those who lost weight or whose weight remained stable. Systolic and diastolic BP and lipids also rose more significantly in the group with weight gain. Conclusions: Although this population of type 2 diabetes in Iran had negligible weight change over mean 9.2 years, this weight gain was associated with an increase in BP and plasma lipids, but also an improvement in glycemic control.
Natural Killer Cells in Psoriasis
Authors: Tobin A.M. , Lynch L. , Kirby B. , O’Farrelly C.
Published: May 2011

Psoriasis is one of the most common immune-mediated disorders. There is evidence that it is mediated by Th1 and, more recently, Th17 cells. The cytokine pattern, particularly the dominance of TNF-α, implicates the innate immune system in psoriasis pathogenesis. Of the many components of the innate immune system known to be involved in psoriatic lesions, natural killer and natural killer T cells appear to have a unique role. We review the evidence supporting a role for natural killer cells in psoriasis.
Laser Ablation of a Large Tongue Hemangioma with Remifentanil Analgosedation in the ORL Endoscopy Suite
Authors: Atkins Joshua H. , Mandel Jeff E. , Mirza Natasha
Published: May 2011

We present a unique, practical, and safe approach to the clinical management of a young male with a large tongue hemangioma who presented for serial surgical treatment of the lesion. Laser ablation was undertaken in the operating room under topical anesthesia with remifentanil analgosedation without the use of supplemental oxygen. Significant involution of the hemangioma was achieved without complication while the patient was awake, cooperative, and able to protect his airway. The application of remifentanil infusion for analgosedation during airway surgery is described. The utility of pharmacokinetic modeling in these applications is discussed along with the use of non-invasive respiratory inductance plethysmography to monitor ventilation during opioid sedation. The concept of analgosedation for airway surgery is introduced and relative risk versus benefit considerations of the approach in comparison to general anesthesia are discussed. This approach can be conceived of as an ORL endoscopy suite model for limited airway procedures.