bluuebunny/crossref_metadata_2025 huggingface dataset:
Polymorphism in Human APOBEC3H Affects a Phenotype Dominant for Subcellular Localization and Antiviral Activity
Authors: Li Melody M. H. , Emerman Michael
Published: June 2011

The APOBEC3 family of cytidine deaminases is part of the innate host defense targeted toward retroviruses and retroelements.
APOBEC3H
is the most distantly related member of the family and carries functional polymorphisms in current human populations. Haplotype II of
APOBEC3H
, which is more commonly found in individuals of African descent, encodes a protein with the highest antiviral activity in cells, whereas the other haplotypes encode proteins with weak or no antiviral activity. Here, we show that the different human
APOBEC3H
haplotypes exhibit differential subcellular localizations, as the haplotype I protein is mostly found in the nucleus and the haplotype II protein is mostly localized to the cytoplasm. The determinant responsible for this phenotype maps to a single amino acid that is also important for APOBEC3H protein stability. Furthermore, we show that the cytoplasmic localization is dominant over nuclear localization, by using fusion proteins of APOBEC3H. Our data support a model in which the APOBEC3H protein encoded by haplotype II is actively retained in the cytoplasm by interacting with specific host factors, whereas the less active protein encoded by haplotype I is allowed to enter the nucleus by a passive mechanism. Together, cytoplasmic localization and its link with protein stability correlate with the ability of APOBEC3H to inhibit HIV replication, providing a mechanistic basis for the differential antiviral activities of different APOBEC3H haplotypes.
Herpes Simplex Virus 1 Glycoprotein B and US3 Collaborate To Inhibit CD1d Antigen Presentation and NKT Cell Function
Authors: Rao Ping , Pham Hong Thanh , Kulkarni Arpita , Yang Yang , Liu Xueqiao , Knipe David M. , Cresswell Peter , Yuan Weiming
Published: June 2011

Herpes simplex viruses (HSVs) are prevalent human pathogens that establish latency in human neuronal cells and efficiently evade the immune system. It has been a major medical challenge to eradicate them and, despite intensive efforts, an effective vaccine is not available. We previously showed that upon infection of antigen-presenting cells, HSV type 1 (HSV-1) rapidly and efficiently downregulates the major histocompatibility complex class I-like antigen-presenting molecule, CD1d, and potently inhibits its recognition by CD1d-restricted natural killer T (NKT) cells. It suppresses CD1d expression primarily by inhibiting its recycling to the cell surface after endocytosis. We identify here the viral glycoprotein B (gB) as the predominant CD1d-interacting protein. gB initiates the interaction with CD1d in the endoplasmic reticulum and stably associates with it throughout CD1d trafficking. However, an additional HSV-1 component, the serine-threonine kinase US3, is required for optimal CD1d downregulation. US3 expression in infected cells leads to gB enrichment in the
trans
-Golgi network (TGN) and enhances the relocalization of both gB and CD1d to this compartment, suggesting that following internalization CD1d is translocated from the endocytic pathway to the TGN by its association with gB. Importantly, both US3 and gB are required for efficient inhibition of CD1d antigen presentation and NKT cell activation. In summary, our results suggest that HSV-1 uses gB and US3 to rapidly inhibit NKT cell function in the initial antiviral response.
Lymphoid aggregates may contribute to the migration and epithelial commitment of bone marrow-derived cells in colonic mucosa
Authors: Valcz Gábor , Krenács Tibor , Sipos Ferenc , Patai Árpád V , Wichmann Barnabás , Leiszter Katalin , Tóth Kinga , Balogh Zsófia , Csizmadia Annamária , Hagymási Krisztina , Masszi Tamás , Molnár Béla , Tulassay Zsolt
Published: June 2011

Aims

Colonic inflammation is followed by regeneration supported by bone marrow-derived cells (BMDCs) including multipotent cells. They migrate to the colonic epithelial layer and may transdifferentiate into epithelial-like cells or keep their stem cell characteristics and produce progenies. The aim was to study the role of lymphoid aggregates in the migration and transition of BMDCs in both healthy colons and non-specific colitis (NSC).

Methods

Samples of normal colon (n=5) and NSC (n=5) from female patients who were initially transplanted with male bone marrow were studied. After detecting XY chromosomes using fluorescent in situ hybridisation, tissue sections were digitalised, the coverslips were eliminated and the samples were double stained for CD45 and cytokeratin with immunofluorescence. Then CDX2 expression, as a sign of intestinal epithelial commitment of Musashi-1+ stromal BMDCs, was also tested with both immunoperoxidase and parallel immunofluorescence stainings. The slides were digitalised again and analysed simultaneously.

Results

A significant increase in intraepithelial CD45–BMDCs was found in regions adjacent to lymphoid aggregates (median: 1.01) compared with healthy epithelial regions (median: 0.0175) or NSC (median: 0.04) samples. The stromal Musashi-1+ cells were positive for CDX2 as well, as a sign of epithelial differentiation. The CDX2+ cells bearing the Y chromosome proved the epithelial commitment of several stromal BMDCs.

Conclusion

Elevated number of intraepithelial CD45−BMDCs at lymphoid aggregates suggests that BMDCs play a role in epithelial regeneration and that lymphoid aggregates serve as their migration route.
mTOR–RAPTOR and 14-3-3σ immunohistochemical expression in high grade prostatic intraepithelial neoplasia and prostatic adenocarcinomas: a tissue microarray study
Authors: Evren Sevan , Dermen Arthur , Lockwood Gina , Fleshner Neil , Sweet Joan
Published: June 2011

Background

The mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase which associates with regulatory-associated protein of TOR (RAPTOR), forming the mTORC1 complex, which is necessary for activation of the mTOR pathway. 14-3-3σ belongs to a family of proteins known to regulate the mTOR–RAPTOR interaction and signalling of this cascade. The mTOR pathway is a key regulator of protein synthesis and growth and is up-regulated in many cancers. The correlation of mTOR, RAPTOR and 14-3-3σ in high grade prostatic intraepithelial neoplasia (HGPIN) and prostate cancer has not previously been investigated.

Aims

To examine the immunohistochemical expression of phosphorylated mTOR (p-mTOR), RAPTOR and 14-3-3σ in HGPIN and prostatic adenocarcinoma (PCa) using tissue microarrays.

Methods and results

There were contrasting immunohistochemical patterns of expression for mTOR and 14-3-3σ in HGPIN and PCa. Cochran–Armitage analysis demonstrated decreasing p-mTOR and increasing 14-3-3σ expression, progressing from PIN through GL6 and GL7 to high grade PCa. In cores with coexistent staining for 14-3-3σ and p-mTOR, the expression of each marker was restricted to different geographical areas of an individual core.

Conclusion

The inverse correlation of p-mTOR and 14-3-3σ expression supports the role of 14-3-3σ as an inhibitor of p-mTOR activity in the prostate. The extent of 14-3-3σ and mTOR expression in an individual patient with prostate cancer would determine how effective the use of mTOR inhibitors would be as potential therapeutic agents.
Sporadic Burkitt lymphoma in southern China: 12 years' experience in a single institution in Guangzhou
Authors: Ye Ziyin , Xiao Yanhua , Shi Huijuan , Ke Zunfu , Liu Yongdong , Liang Yingjie , Han Anjia
Published: June 2011

Aim

To analyse the clinicopathological features of sporadic Burkitt lymphoma (sBL).

Methods

In a review of 1682 cases of non-Hodgkin lymphoma diagnosed in the First Affiliated Hospital and Zhongshan School of Medicine, from 1998 to 2010, 20 cases (1.2%) of sBL were identified. Histopathological examination, immunohistochemistry and in situ hybridisation were used to analyse the clinicopathological features of these cases.

Results

Of the 20 cases of sBL, 18 patients were male and two were female. The mean age was 18 years (range 2–67 years). Extranodal presentation was more common than nodal presentation (55% vs 15%). Histopathologically, 18 cases (90%) showed monotonous medium-sized tumour cells, and two cases showed cells that were slightly pleomorphic in nuclear size and shape. Immunophenotypically, MUM1 was positive in three of 17 cases (17.6%). EBER expression was shown in five of 17 cases (29.4%), and all EBER-positive sBLs were Bcl-6+/MUM1−.

Conclusion

sBL is rare and mainly affects male children, with predominantly extranodal presentation. MUM1 expression was found in some sBLs. EBER expression was found in 29.4% of sBLs from southern China, an area with a well-known high incidence of nasopharyngeal carcinoma, which is closely associated with Epstein–Barr virus infection.
GALILEAN TYPE IIA BACKGROUNDS AND A MAP
Authors: SINGH HARVENDRA
Published: June 2011

We study nonrelativistic AdS4×CP3 solutions with dynamical exponent 3 in type IIA string theory, both with and without Romans mass. The compactifications to four dimensions are found to describe Proca fields in anti-de Sitter spacetime. This leads us to conclude that the massive and massless IIA theories should be identified in four dimensions and the Romans' mass should be identified with the "flux" along CP3. From supergravity point of view, it suggests a four-dimensional symmetry that rotates Romans mass into the flux along CP3. We also identify M-theory Galilean (ABJM) background which gives rise to the nonrelativistic type IIA solution.
LAYER-BY-LAYER SELF-ASSEMBLED FILMS OF ROSE BENGAL
Authors: HUSSAIN S. A. , DEY D. , BHATTACHARJEE D.
Published: June 2011

Layer-by-Layer (LBL) self-assembled films of rose bengal (RB) have been fabricated onto quartz substrate by the alternative adsorption of polycation poly (amine hydrochloride) (PAH) and RB. UV–Vis absorption studies reveal the formation of RB dimmer in PAH-RB LbL films. Scanning Electron Micrograph (SEM) picture confirms the aggregation of RB molecules in LbL films. Almost 15 min is required to complete the interaction between RB and PAH molecules in the 1 bilayer LbL film. The dye (RB) was found to come off the film during the subsequent poly cation (PAH) deposition. As an alternative approach RB was anchored to the polycation PAH via physiadsorption and controlling the concentration of the combination of RB and PAH was used as polycation and poly (acrylic acid) (PAA) as polyanion for film deposition. The absorption spectra after each deposition showed that there was no material loss during layer depositions via second method.
REALIZING OPEN-DESTINATION AND CONTROLLED TELEPORTATION OF A ROTATION USING PARTIALLY ENTANGLED PAIRS
Authors: CHEN LI-BING , JIN RUI-BO , PENG TAN , LU HONG
Published: June 2011

We present a scheme for realizing open-destination and controlled teleportation of a single-qubit rotation gate, albeit probabilistically, by using partially entangled pairs of particles. In the scheme, a quantum rotation is faithfully teleported onto any one of N spatially separated receivers under the control of the (N-1) unselected receivers in a network. We first present the three-destination and controlled teleportation of a rotation gate by using three partially entangled pairs, and then generalize the scheme to the case of N-destination. In our scheme, the sender's local generalized measurement described by a positive operator-valued measurement (POVM) lies at the heart. We construct the required POVM. The fact that deterministic and exact teleportation of a rotation gate could be realized using partially entangled pairs is notable.
ROBUST SYNCHRONIZATION OF CHAOTIC SYSTEMS USING ACTIVE SLIDING MODE CONTROL WITH MINIMUM CONTROL EFFORT
Authors: NASEH MAJID REZA , HAERI MOHAMMAD
Published: June 2011

oActive sliding mode control is one of the effective methods to synchronize chaotic systems in the presence of uncertainties. Use of the method, however, requires decision making on how to choose the control parameters for a specific performance. In this paper we propose an algorithm to determine the best control parameters for which the minimum control efforts are required to synchronize two identical or non-identical chaotic systems. We have also determined the maximum range of the uncertainties on which the selected control parameters to work properly. The effectiveness of the proposed method has been verified through numerical simulations.
ŠIL'NIKOV HOMOCLINIC ORBITS IN TWO CLASSES OF 3D AUTONOMOUS NONLINEAR SYSTEMS
Authors: CHEN BAOYING , ZHOU TIANSHOU
Published: June 2011

The Šil'nikov homoclinic theorem provides one analytic criterion for proving the existence of chaos in three-dimensional autonomous nonlinear systems. In applications of the theorem, however, the existence of a homoclinic orbit that usually determines the geometric structure of the chaotic attractor is not easily verified mainly because there are no available efficient methods. In this paper, based on the undetermined coefficient approach we present a framework of how to find homoclinic orbits in two classes of three-dimensional autonomous nonlinear systems of normal forms, including how to set a reasonable form of expanding series of the homoclinic orbit, how to determine all coefficients in the expansion, and how to find a numerical homoclinic orbit. Numerical examples show that the proposed framework in combination with computer simulation is very efficient.
ISOTYPE SnO2–Si HETEROJUNCTION MADE BY RAPID PHOTOTHERMAL OXIDATION OF Sn
Authors: ISMAIL RAID A. , SHEEL MAHDI H. , GHAFORI SA'AD
Published: June 2011

We report on fabrication and characterization of SnO 2– Si n–n made by deposition of SnO 2 film onto monocrystalline silicon substrate by rapid photothermal oxidation (RPO) of Sn with condition 500°C/120 s. The film has been characterized by techniques such as XRD, optical transmission, and Hall effect. The XRD spectrum showed that the grown SnO 2 was polycrystalline in nature with tetragonal crystal structure. From optical transmittance data the band gap of SnO 2 film was calculated and found to be 3.9 eV. The electrical measurement revealed that the SnO 2 film was n-type. Current–voltage (I–V) and capacitance–voltage (C–V) characteristics of SnO 2– Si heterojunction were investigated. The ideality factor of junction estimated from I–V characteristics was 1.8 at 300 K. The spectral responsivity of heterojunction having two peaks of response located at 650 nm and 850 nm.
AN ALGEBRAIC STRUCTURE OF ZERO CURVATURE REPRESENTATIONS ASSOCIATED WITH COUPLED INTEGRABLE COUPLINGS AND APPLICATIONS TO τ-SYMMETRY ALGEBRAS
Authors: LUO LIN , MA WEN-XIU , FAN ENGUI
Published: June 2011

We establish an algebraic structure for zero curvature representations of coupled integrable couplings. The adopted zero curvature representations are associated with Lie algebras possessing two sub-Lie algebras in form of semi-direct sums of Lie algebras. By applying the presented algebraic structures to the AKNS systems, we give an approach for generating τ-symmetry algebras of coupled integrable couplings.
T–S FUZZY ADAPTIVE DELAYED FEEDBACK SYNCHRONIZATION FOR TIME-DELAYED CHAOTIC SYSTEMS WITH UNCERTAIN PARAMETERS
Authors: AHN CHOON KI , KIM PYUNG SOO
Published: June 2011

In this paper, we propose a new adaptive synchronization method, called a fuzzy adaptive delayed feedback synchronization (FADFS) method, for time-delayed chaotic systems with uncertain parameters. An FADFS controller that is based on the Lyapunov–Krasovskii theory, Takagi–Sugeno (T–S) fuzzy model, and delayed feedback control is developed to guarantee adaptive synchronization. The proposed controller can be obtained by solving the linear matrix inequality (LMI) problem. A numerical example using a time-delayed Lorenz system is discussed to assess the validity of the proposed FADFS method.
THE NEGATIVE PERMITTIVITY AND PERMEABILITY CHARACTERISTICS OF TRIANGULAR ELECTROMAGNETIC RESONATORS
Authors: ZHU C. , LI L. , LIANG C. H.
Published: June 2011

In this paper, the triangular electromagnetic resonators (TERs) is introduced and investigated. The electric mode at lower frequency and magnetic mode at higher frequency, originating from coupling to the electric field and magnetic field, are validated through the measurement in parallel-plate waveguide system, parameter retrieval algorithm and surface currents distributions. Besides, the double negative properties of TERs-wire structures have been validated through both transmission experiment and phase shift experiment. This new resonators with distinct electric resonance as well as magnetic resonance could provide us a new way to design double negative material.
EFFECTS OF TRANSVERSE MAGNETIC FIELD ON THE PERISTALTIC TRANSPORT OF VISCOELASTIC FLUID WITH JEFFREY MODEL IN A FINITE LENGTH CHANNEL
Authors: TRIPATHI D. , HAYAT T. , ALI N. , PANDEY S. K.
Published: June 2011

This paper investigates the peristaltic flow of viscoelastic fluid represented by Jeffrey model in presence of transverse magnetic field under long wavelength and low Reynolds number assumptions. The expressions of pressure gradient, volume flow rate, average volume flow rate and local wall shear stress are obtained. The effects of transverse magnetic field, electrical conductivity (i.e., Hartman number M), relaxation time and retardation time on pressure difference, local wall shear stress, and mechanical efficiency of peristaltic pump are discussed. Reflux limit for viscoelastic fluid is also found and the effects of all parameters on reflux phenomena are discussed. Comparative study of integral and nonintegral number of waves propagate in a train is presented.
Investor Psychological and Behavioral Bias: Do High Sentiment and Momentum Exist in the China Stock Market?
Authors: Li Chun-An , Yeh Chih-Cheng
Published: June 2011

By using the relationship between high sentiment and momentum, the main purpose of this paper is to investigate if psychological biases of investors have an influence on behavioral biases. We find that in the China stock market, high sentiment of loser groups is correlated with contributors of momentum profits, while high sentiment of winner groups is correlated with contributors of contrarian returns. Further analysis indicates that, the higher the investor psychological bias is, the greater the momentum return will become. Winners/losers that are most sensitive to sentiment and having the longest duration of being kept under the situation will result in higher returns.
Real-time observation of flow-induced cytoskeletal stress in living cells
Authors: Rahimzadeh Jason , Meng Fanjie , Sachs Fredrick , Wang Jianbin , Verma Deepika , Hua Susan Z.
Published: June 2011

The mechanical stress due to shear flow has profound effects on cell proliferation, transport, gene expression, and apoptosis. The mechanisms for flow sensing and transduction are unclear, but it is postulated that fluid flow pulls upon the apical surface, and the resulting stress is eventually transmitted through the cytoskeleton to adhesion plaques on the basal surface. Here we report a direct observation of this flow-induced stress in the cytoskeleton in living cells using a parallel plate microfluidic chip with a fluorescence resonance energy transfer (FRET)-based mechanical stress sensor in actinin. The sensing cassette was genetically inserted into the cytoskeletal host protein and transfected into Madin-Darby canine kidney cells. A shear stress of 10 dyn/cm2 resulted in a rapid increase in the FRET ratio indicating a decrease in stress across actinin with flow. The effect was reversible, and cells were able to respond to repeated stimulation and showed adaptive changes in the cytoskeleton. Flow-induced Ca2+ elevation did not affect the response, suggesting that flow-induced changes in actinin stress are insensitive to intracellular Ca2+ level. The reduction in FRET ratio suggests actin filaments are under normal compression in the presence of flow shear stress due to changes in cell shape, and/or actinin is not in series with actin. Treatment with cytochalasin-D that disrupts F-actin reduced prestress and the response to flow. The FRET/flow method is capable of resolving changes of stress in multiple proteins with optical spatial resolution and time resolution >1 Hz. This promises to provide insight into the force distribution and transduction in all cells.
Regulation of VEGF-induced endothelial cell migration by mitochondrial reactive oxygen species
Authors: Wang Youxue , Zang Qun S. , Liu Zijuan , Wu Qian , Maass David , Dulan Genevieve , Shaul Philip W. , Melito Lisa , Frantz Doug E. , Kilgore Jessica A. , Williams Noelle S. , Terada Lance S. , Nwariaku Fiemu E.
Published: June 2011

Endothelial migration is a crucial aspect of a variety of physiologic and pathologic conditions including atherosclerosis and vascular repair. Reactive oxygen species (ROS) function as second messengers during endothelial migration. Multiple intracellular sources of ROS are regulated by cellular context, external stimulus, and the microenvironment. However, the predominant source of ROS during endothelial cell (EC) migration and the mechanisms by which ROS regulate cell migration are incompletely understood. In this study, we tested the hypothesis that mitochondria-derived ROS (mtROS) regulate EC migration. In cultured human umbilical vein endothelial cells, VEGF increased mitochondrial metabolism, promoted mtROS production, and induced cell migration. Either the targeted mitochondrial delivery of the antioxidant, vitamin E (Mito-Vit-E), or the depletion of mitochondrial DNA abrogated VEGF-mediated mtROS production. Overexpression of mitochondrial catalase also inhibited VEGF-induced mitochondrial metabolism, Rac activation, and cell migration. Furthermore, these interventions suppressed VEGF-stimulated EC migration and blocked Rac1 activation in endothelial cells. Constitutively active Rac1 reversed Mito-Vit-E-induced inhibition of EC migration. Mito-Vit-E also attenuated carotid artery reendothelialization in vivo. These results provide strong evidence that mtROS regulate EC migration through Rac-1.
Contributions of VEGF to age-dependent transmural gradients in contractile protein expression in ovine carotid arteries
Authors: Butler Stacy M. , Abrassart Jenna M. , Hubbell Margaret C. , Adeoye Olayemi , Semotiuk Andrew , Williams James M. , Mata-Greenwood Eugenia , Khorram Omid , Pearce William J.
Published: June 2011

The present study explores the hypothesis that arterial smooth muscle cells are organized into layers with similar phenotypic characteristics that vary with the relative position between the lumen and the adventitia due to transmural gradients in vasotrophic factors. A corollary hypothesis is that vascular endothelial growth factor (VEGF) is a factor that helps establish transmural variations in smooth muscle phenotype. Organ culture of endothelium-denuded ovine carotid arteries with 3 ng/ml VEGF-A165 for 24 h differentially and significantly influenced potassium-induced (55% increase) and stretch-induced (36% decrease) stress-strain relations in adult ( n = 18) but not term fetal ( n = 21) arteries, suggesting that smooth muscle reactivity to VEGF is acquired during postnatal maturation. Because inclusion of fetal bovine serum significantly inhibited all contractile effects of VEGF (adult: n = 11; fetus: n = 11), it was excluded in all cultures. When assessed in relation to the distance between the lumen and the adventitia in immunohistochemically stained coronal artery sections, expression of smooth muscle α-actin (SMαA), myosin light chain kinase (MLCK), and 20-kDa regulatory myosin light chain exhibited distinct protein-dependent and age-dependent gradients across the artery wall. VEGF depressed regional SMαA abundance up to 15% in adult ( n = 6) but not in fetal ( n = 6) arteries, increased regional MLCK abundance up to 140% in fetal ( n = 8) but not in adult ( n = 10) arteries, and increased regional MLC20 abundance up to 28% in fetal arteries ( n = 7) but decreased it by 17% in adult arteries ( n = 9). Measurements of mRNA levels verified that VEGF receptor transcripts for both Flt-1 and kinase insert domain receptor (KDR) were expressed in both fetal and adult arteries. Overall, the present data support the unique hypothesis that smooth muscle cells are organized into lamina of similar phenotype with characteristics that depend on the relative position between the lumen and the adventitia and involve the direct effects of growth factors such as VEGF, which acts independently of the vascular endothelium in an age-dependent manner.
Digestive physiology: a view from molecules to ecosystem
Authors: Karasov William H.
Published: June 2011

Digestive physiology links physiology to applications valued by society, such as understanding ecology and ecological toxicology and managing and conserving species. Here I illustrate this applied and integrative perspective with several avian case studies. The match between digestive features and diet provides evidence of tradeoffs that preclude doing well on all possible substrates with a single digestive design, and this influences ecological niche partitioning. But some birds, such as wild house sparrow ( Passer domesticus ) nestlings, are digestively very flexible. Their intestinal maltase activity and mRNA for intestinal maltase glucoamylase specifically and reversibly change when they switch among foods with different starch content. Houses sparrows and many other birds absorb hydrolyzed water-soluble monomers, such as glucose, mainly passively via tight junctions between enterocytes (i.e., paracellular absorption). Such species might be good models for studying this process, which is important biomedically for absorption of drugs. High paracellular absorption may enhance absorption of low molecular weight, natural water-soluble toxins. Also, reliance of American robins ( Turdus migratorius ) on passive absorption makes them less sensitive to types of plant toxins that inhibit mediated glucose absorption, such as phlorizin or the flavanoid isoquercetrin. Determining absorption of environmental contaminants is another important ecological application. Common loon ( Gavia immer ) chicks absorbed 83% of methyl mercury in fish meals, eliminate the mercury slowly, and consequently are predicted in the wild to bioaccumulate mercury to higher concentrations than in their foods. The quantitative details can be used to set regulatory levels for mercury that will protect wildlife.
Nicotine excites hypothalamic arcuate anorexigenic proopiomelanocortin neurons and orexigenic neuropeptide Y neurons: similarities and differences
Authors: Huang Hao , Xu Youfen , van den Pol Anthony N.
Published: June 2011

Two of the biggest health problems facing us today are addiction to nicotine and the increased prevalence of obesity. Interestingly, nicotine attenuates obesity, but the underlying mechanism is not clear. Here we address the hypothesis that if weight-reducing actions of nicotine are mediated by anorexigenic proopiomelanocortin (POMC) neurons of the hypothalamic arcuate nucleus, nicotine should excite these cells. Nicotine at concentrations similar to those found in smokers, 100–1,000 nM, excited POMC cells by mechanisms based on increased spike frequency, depolarization of membrane potential, and opening of ion channels. This was mediated by activation of both α7 and α4β2 nicotinic receptors; by itself, this nicotine-mediated excitation could explain weight loss caused by nicotine. However, in control experiments nicotine also excited the orexigenic arcuate nucleus neuropeptide Y (NPY) cells. Nicotine exerted similar actions on POMC and NPY cells, with a slightly greater depolarizing action on POMC cells. Immunocytochemistry revealed cholinergic axons terminating on both cell types. Nicotine actions were direct in both cell types, with nicotine depolarizing the membrane potentials and reducing input resistance. We found no differences in the relative desensitization to nicotine between POMC and NPY neurons. Nicotine inhibited excitatory synaptic activity recorded in NPY, but not POMC, cells. Nicotine also excited hypocretin/orexin neurons that enhance cognitive arousal, but the responses were smaller than in NPY or POMC cells. Together, these results indicate that nicotine has a number of similar actions, but also a few different actions, on POMC and NPY neurons that could contribute to the weight loss associated with smoking.
Modules in the brain stem and spinal cord underlying motor behaviors
Authors: Roh Jinsook , Cheung Vincent C. K. , Bizzi Emilio
Published: June 2011

Previous studies using intact and spinalized animals have suggested that coordinated movements can be generated by appropriate combinations of muscle synergies controlled by the central nervous system (CNS). However, which CNS regions are responsible for expressing muscle synergies remains an open question. We address whether the brain stem and spinal cord are involved in expressing muscle synergies used for executing a range of natural movements. We analyzed the electromyographic (EMG) data recorded from frog leg muscles before and after transection at different levels of the neuraxis—rostral midbrain (brain stem preparations), rostral medulla (medullary preparations), and the spinal-medullary junction (spinal preparations). Brain stem frogs could jump, swim, kick, and step, while medullary frogs could perform only a partial repertoire of movements. In spinal frogs, cutaneous reflexes could be elicited. Systematic EMG analysis found two different synergy types: 1) synergies shared between pre- and posttransection states and 2) synergies specific to individual states. Almost all synergies found in natural movements persisted after transection at rostral midbrain or medulla but not at the spinal-medullary junction for swim and step. Some pretransection- and posttransection-specific synergies for a certain behavior appeared as shared synergies for other motor behaviors of the same animal. These results suggest that the medulla and spinal cord are sufficient for the expression of most muscle synergies in frog behaviors. Overall, this study provides further evidence supporting the idea that motor behaviors may be constructed by muscle synergies organized within the brain stem and spinal cord and activated by descending commands from supraspinal areas.
Polysynaptic excitatory postsynaptic potentials that trigger spasms after spinal cord injury in rats are inhibited by 5-HT1B and 5-HT1F receptors
Authors: Murray Katherine C. , Stephens Marilee J. , Rank Michelle , D'Amico Jessica , Gorassini Monica A. , Bennett David J.
Published: June 2011

Sensory afferent transmission and associated spinal reflexes are normally inhibited by serotonin (5-HT) derived from the brain stem. Spinal cord injury (SCI) that eliminates this 5-HT innervation leads to a disinhibition of sensory transmission and a consequent emergence of unusually long polysynaptic excitatory postsynaptic potentials (EPSPs) in motoneurons. These EPSPs play a critical role in triggering long polysynaptic reflexes (LPRs) that initiate muscles spasms. In the present study we examined which 5-HT receptors modulate the EPSPs and whether these receptors adapt to a loss of 5-HT after chronic spinal transection in rats. The EPSPs and associated LPRs recorded in vitro in spinal cords from chronic spinal rats were consistently inhibited by 5-HT1B or 5-HT1F receptor agonists, including zolmitriptan (5-HT1B/1D/1F) and LY344864 (5-HT1F), with a sigmoidal dose-response relation, from which we computed the 50% inhibition (EC50) and potency (−log EC50). The potencies of 5-HT receptor agonists were highly correlated with their binding affinity to 5-HT1B and 5-HT1F receptors, and not to other 5-HT receptors. Zolmitriptan also inhibited the LPRs and general muscle spasms recorded in vivo in the awake chronic spinal rat. The 5-HT1B receptor antagonists SB216641 and GR127935 and the inverse agonist SB224289 reduced the inhibition of LPRs by 5-HT1B agonists (zolmitriptan). However, when applied alone, SB224289, SB216641, and GR127935 had no effect on the LPRs, indicating that 5-HT1B receptors do not adapt to chronic injury, remaining silent, without constitutive activity. The reduction in EPSPs with zolmitriptan unmasked a large glycine-mediated inhibitory postsynaptic current (IPSC) after SCI. This IPSC and associated chloride current reversed at −73 mV, slightly below the resting membrane potential. Zolmitriptan did not change motoneuron properties. Our results demonstrate that 5-HT1B/1F agonists, such as zolmitriptan, can restore inhibition of sensory transmission after SCI without affecting general motoneuron function and thus may serve as a novel class of antispastic drugs.
Enhanced Metastasis Suppression by Targeting TRAIL Receptor 2 in a Murine Model of Triple-Negative Breast Cancer
Authors: Malin Dmitry , Chen Feng , Schiller Carol , Koblinski Jennifer , Cryns Vincent L.
Published: June 2011

Purpose: Metastatic breast cancer is a deadly disease which requires new therapeutic strategies. Endogenous TNF-related apoptosis-inducing ligand (TRAIL) functions as a metastasis suppressor by activating proapoptotic TRAIL receptors (TRAIL-R1/DR4 and/or TRAIL-R2/DR5) in transformed cells, making it an attractive pathway for antimetastatic therapies. However, it is unclear whether TRAIL-R1 or TRAIL-R2 is a better therapeutic target in metastatic breast cancer.

Experimental Design: Several metastatic, triple (estrogen receptor, progesterone receptor, and HER2)-negative cancer cell lines were treated with human agonistic monoclonal antibodies targeting TRAIL-R1 (mapatumumab) or TRAIL-R2 (lexatumumab). The effects on cell viability, apoptosis, and caspase-8 activation were determined. An orthotopic model of triple-negative breast cancer in which fluorescently labeled breast cancer cells metastasize from the mammary gland to lymph nodes and lung was utilized to evaluate the effects of mapatumumab, lexatumumab, or doxorubicin on primary and metastatic tumor burden in vivo.

Results: Lexatumumab was more effective than mapatumumab in activating caspase-8, inducing apoptosis and inhibiting long-term survival of metastatic cancer cells, which expressed both TRAIL-R1 and TRAIL-R2. Human mammary epithelial cells transformed by oncogenic Ras were more sensitive to lexatumumab than nontransformed cells. Lexatumumab inhibited lymph node and lung metastases more robustly than mapatumumab in an orthotopic model of triple-negative breast cancer; both agents inhibited mammary tumor growth. In addition, lexatumumab was more effective than doxorubicin at suppressing metastases at doses of doxorubicin that were associated with toxicity, even though doxorubicin reduced primary tumor burden more robustly than lexatumumab.

Conclusion: Targeting TRAIL-R2 receptor may be an effective therapeutic strategy for metastatic breast cancer. Clin Cancer Res; 17(15); 5005–15. ©2011 AACR.
Enhanced Antitumor Effects by Chemical Modified IGb3 Analogues
Authors: Zhou Zhixia , Zhang Cai , Xia Chengfeng , Chen Wenlan , Zhu Huawei , Shang Pingping , Ma Fang , Wang Peng George , Zhang Jian , Xu Wenfang , Tian Zhigang
Published: June 2011

Certain glycolipid antigens for natural killer T (NKT) cells can direct the overall cytokine balance of the immune response. However, the molecular mechanism of Th1- or Th2-biased cytokine secretion by NKT cells is still unknown. Previously, we synthesized isoglobotrihexosylceramide (iGb3) analogues by introducing a hydroxyl group at C4 on the ceramide portion of iGb3 to produce 4-HO-iGb3 or to further deoxylation on the terminal galactose to produce 4‴-dh-iGb3. Both modified iGb3, especially 4‴-dh-iGb3, stimulated more IFN-γ production by hepatic NKT cells, and thus elicited preferential Th1 responses. Here, we found that 4‴-dh-iGb3–loaded bone marrow–derived dendritic cells (DC) could significantly inhibit growth of subcutaneous melanoma and suppress lung metastasis in C57BL/6 mice compared with unmodified iGb3-loaded DCs. In investigating the mechanisms of this improved activity, we found that 4‴-dh-iGb3 stimulation increased STAT1 signaling by NKT cells, whereas the phosphorylation of Th2 type cytokine–associated transcription factor STAT6 signaling was not affected. Analysis of the structures of iGb3 and 4‴-dh-iGb3 revealed that 4‴-dh-iGb3 provides greater stability and affinity between glycolipid and CD1d or NKT TCR complex than iGb3. Thus, 4‴-dh-iGb3 can improve the antitumor effects of a DC-based vaccine possibly by stabilizing the CD1d/glycolipid/TCR complex and stimulating IFN-γ signaling of NKT cells. Furthermore, chemical modification of iGb3 can elicit Th1-biased responses by NKT cells, and 4‴-dh-iGb3 combined with a DC vaccine may serve as a potent new NKT-based therapy against tumors and infectious diseases. Mol Cancer Ther; 10(8); 1375–84. ©2011 AACR.
B Chromosomes and Sex in Animals
Authors: Camacho J.P.M. , Schmid M. , Cabrero J.
Published: June 2011

Supernumerary (B) chromosomes are dispensable elements found in many eukaryote genomes in addition to standard (A) chromosomes. In many respects, B chromosomes resemble sex chromosomes, so that a common ancestry for them has frequently been suggested. For instance, B chromosomes in grasshoppers, and other insects, show a pycnotic cycle of condensation-decondensation during meiosis remarkably similar to that of the X chromosome. In some cases, B chromosome size is even very similar to that of the X chromosome. These resemblances have led to suggest the X as the B ancestor in many cases. In addition, sex chromosome origin from B chromosomes has also been suggested. In this article, we review the existing evidence for both evolutionary pathways, as well as sex differences for B frequency at adult and embryo progeny levels, B chromosome effects or B chromosome transmission. In addition, we review cases found in the literature showing sex-ratio distortion associated with B chromosome presence, the most extreme case being the paternal sex ratio (PSR) chromosomes in some Hymenoptera. We finally analyse the possibility of B chromosome regularisation within the host genome and, as a consequence of it, whether B chromosomes can become regular members of the host genome.
Are Stalkers Disordered or Criminal? Thoughts on the Psychopathology of Stalking
Authors: Dressing Harald , Foerster Klaus , Gass Peter
Published: June 2011

Although stalking is a widespread phenomenon that can be caused by different motives, consideration of the psychopathological underpinnings of stalking behaviour is scarce. In rare cases, stalking can be an expression of mental disorder. Psychotic stalking, for example, can occur as a symptom of schizophrenia or erotomania. Psychotic stalkers are criminally not responsible for their acts and have to be treated in a psychiatric hospital. The majority of stalkers, however, do not suffer from a disorder in need of treatment, and therefore their criminal responsibility is not diminished. Although legislative approaches to protecting victims of stalking differ widely in the European Union, mentally not severely disturbed stalkers can be prosecuted and punished according to criminal law in most countries. In some cases, the differentiation between mentally sane and mentally disturbed stalkers is difficult. This paper focuses on the psychopathology of such ‘borderline cases’, using the example of a court decision in Germany.
Fibroblast Growth Factor-9 in Marsupial Testicular Development
Authors: Chung J.W. , Pask A.J. , Yu H. , Renfree M.B.
Published: June 2011

FGF9 is a member of the fibroblast growth factor (FGF) family and is critical for early testicular development and germ cell survival in the mouse. Fgf9 reinforces the testis determinant Sox9 and antagonizes Wnt4, an ovarian factor. To determine whether FGF9 has a conserved role in the mammalian gonad, we examined its expression in the gonads of a marsupial, the tammar wallaby Macropus eugenii, and compared it to WNT4 expression. Marsupial FGF9 is highly conserved with orthologues from eutherian mammals, including humans. FGF9 protein was detected in both the testis and ovary before sexual differentiation, but it subsequently became sexually dimorphic during the period of testicular differentiation. The protein was specifically enriched in the seminiferous cords of the developing testis in the Sertoli and germ cells. FGF9 mRNA expression was upregulated in the tammar testis at the time of seminiferous cord formation and downregulated in the developing ovary in an opposite profile to that of marsupial WNT4. These observations suggest that FGF9 promotes male fate in the early gonad of marsupials through an antagonistic relationship with WNT4 as it does in eutherian mammals.
The Geneva Appetitive Alcohol Pictures (GAAP): Development and Preliminary Validation
Authors: Billieux Joël , Khazaal Yasser , Oliveira Sandrine , de Timary Philippe , Edel Yves , Zebouni Fadi , Zullino Daniele , Van der Linden Martial
Published: June 2011

This study describes a new database of alcohol-related pictures: The Geneva Appetitive Alcohol Pictures (GAAP). 60 alcohol-related pictures (beverages, drinking-related behaviors, alcohol-related cues) were presented to 101 participants (ranging from social drinkers to problem drinkers), who assessed them according to the classic emotional pictures validation provided by the International Affective Picture System (Center for the Study of Emotion and Attention (CSEA[-]NIMH), 2002). Participants were also screened with the Alcohol Use Disorders Identification Test. Normative ratings for valence, arousal and dominance of the pictures are provided separately for problem/risky users (n = 49) and non-risky drinkers (n = 52). The GAAP is a normative database that provides a large number of stimuli for investigators who conduct research on alcohol.
Reproducibility of and Correspondence among Different Hepcidin Forms in Blood and Urine and Their Relationships to Iron Status in Healthy, Male Guatemalan Volunteers Observed over 9 Weeks
Authors: Schuemann Klaus , Solomons Noel W. , Laarakkers Coby M. , Romero-Abal María-Eugenia , Kroll Sylvia , Weiss Guenter , Swinkels Dorine W.
Published: June 2011

Background/Aims: Prohepcidin and the active form hepcidin-25 are two variants of the peptide hormone hepcidin for iron homoeostasis. Their regulatory role and usefulness as biomarkers of the iron status are uncertain. Our aim is to describe the intra-individual variance of serum and urinary hepcidin-25 and prohepcidin concentrations, the mutual associations of the 4 hepcidin formats, and their correspondence with iron status variables in male Guatemalan volunteers. Methods: Eight healthy adult males provided serial samples of serum and urine without previous iron dosing over 6 intervals during a 9-week protocol period. Prohepcidin was assayed by a commercial enzyme immunoassay, and hepcidin-25 species in serum and urine were analysed by time-of-flight mass spectrometry after prior enrichment procedures. Results: Serum hepcidin-25 levels correlated significantly with urinary hepcidin-25 concentrations, whereas serum and urinary prohepcidin were not associated with one another or with the homologous or converse formats for hepcidin-25. Serum ferritin and transferrin saturation were significantly correlated with serum hepcidin-25 concentrations, but not with urine hepcidin-25 or with either format of prohepcidin. Conclusion: Hepcidin-25 shows correspondence across biological fluids, and the background ‘status’ of hepcidin activation may be related to the host’s iron stores, whereas prohepcidin concentrations showed no promise in this regard.
The in vitro effect of the new antithrombotic drug candidate ALX-0081 on blood samples of patients undergoing percutaneous coronary intervention
Authors: Loon Janine E. van , Jaegere Peter P. T de , Vliet Huub H. D. M van , Maat Moniek P. M de , de Groot Philip G. , Simoons Maarten L. , Leebeek Frank W. G.
Published: June 2011

Compound ALX-0081 is a bivalent humanised Nanobody® that binds the A1-domain of von Willebrand factor (VWF) with high affinity. Consequently, it can block the interaction between VWF and its platelet-receptor- glycoprotein Ib, which leads inevitably to formation of arterial thrombi. It was the objective of this study to assess the in vitro effects of ALX-0081 on platelet adhesion and aggregation in coronary artery disease (CAD) patients to determine the optimal concentration of ALX-0081 and the effect of co-medication. We included nine CAD patients, who were scheduled for elective percutaneous coronary intervention (PCI), and 11 healthy volunteers. At admission all patients received aspirin, clopidogrel and heparin. Blood was drawn 24 hours (h) before and 1 h after start of the PCI procedure and was subsequently spiked with different concentrations of ALX-0081 or buffer. The efficacy of ALX-0081 was assessed by in vitro experiments: flow chamber experiments, ristocetin-induced platelet aggregation (RIPA), and the platelet function analyser (PFA-100TM). VWF levels in CAD patients were significantly higher than in healthy controls. During PCI VWF levels did not rise. In all in vitro experiments, ALX-0081 led to complete inhibition of platelet adhesion and aggregation. However, the required effective concentration was higher in patients than in controls and was related to plasma VWF levels. In conclusion, ALX-0081 is able to completely inhibit in vitro platelet adhesion and aggregation in CAD patients scheduled for elective PCI. The efficacy of ALX-0081 is not influenced by PCI or co-medication. However, due to higher VWF levels in CAD patients a higher effective concentration of ALX-0081 was required than in healthy individuals.
Early determination of clopidogrel responsiveness by platelet reactivity index identifies patients at risk for cardiovascular events after myocardial infarction
Authors: Schäfer Andreas , Flierl Ulrike , Kössler Jürgen , Seydelmann Nora , Kobsar Anna , Störk Stefan , Bauersachs Johann
Published: June 2011

While acute myocardial infarction (MI) is associated with impaired clopidogrel responsiveness, systematic evaluation is lacking due to the inability of functional aggregation-based assays to analyse clopidogrel responsiveness in the presence of glycoprotein IIb/IIIa inhibitors. Using the P2Y12-specific, non-aggregation-based platelet-reactivity-index (PRI) we assessed clopidogrel responsiveness in patients with acute MI. Clopidogrel responsiveness was determined 24 hours (h) after loading with 600 mg clopidogrel in 54 patients with acute MI admitted for coronary intervention. A PRI > 50% was considered as suboptimal inhibition. Overall response in MI patients was suboptimal with a median PRI of 58%. Diabetes, low high-density lipoprotein and pre-hospital clopidogrel loading were associated with impaired clopidogrel responsiveness. Patients loaded at first medical contact had a significantly weaker platelet inhibition by clopidogrel after 24 h (PRI 63%) compared to those loaded peri-interventionally (PRI 54%, p=0.014). Clinical outcome was assessed as a combination of cardiac death, non-fatal MI, stent thrombosis, ischaemic stroke, and urgent target vessel revascularisation after 12 months. The pre-selected cut-off of PRI ≤ 50% yielded a sensitivity of 87% at a specificity of 26%, whereas a PRI ≤ 57% determined by receiver-operating characteristics (ROC)-analysis yielded a sensitivity of 80% at a specificity of 56% (event rate: PRI ≤ 57%: 12.0%; PRI > 57%: 41.4%, p=0.0136). In conclusion, PRI detects clopidogrel responsiveness in acute MI patients requiring glycoprotein IIb/IIIa antagonism; and impaired clopidogrel responsiveness predisposes to clinical events. Pre-hospital clopidogrel loading was associated with impaired response and more adverse events challenging the concept of earliest oral clopidogrel loading in MI patients.