bluuebunny/crossref_metadata_2025 huggingface dataset:
pO157_Sal, a Novel Conjugative Plasmid Detected in Outbreak Isolates of Escherichia coli O157:H7
Authors: Wang Ping , Xiong Yanwen , Lan Ruiting , Ye Changyun , Wang Hua , Ren Jun , Jing Huaiqi , Wang Yiting , Zhou Zhemin , Cui Zhigang , Zhao Hongqing , Chen Yuli , Jin Dong , Bai Xuemei , Zhao Ailan , Wang Yan , Zhang Shaomin , Sun Hui , Li Juan , Wang Tao , Wang Lei , Xu Jianguo
Published: February 2011

In addition to the large virulence plasmid pO157, a novel 38-kb conjugative plasmid, pO157_Sal, was identified and sequenced from an
Escherichia coli
O157:H7 outbreak-associated Chinese isolate that shares high similarity with a plasmid in
Salmonella enterica
serovar Agona. The plasmid was found in 15 of 326 isolates, 12 of which were of the same pulsed-field gel electrophoresis type.
Mobility and Interactions of Coronavirus Nonstructural Protein 4
Authors: Hagemeijer Marne C. , Ulasli Mustafa , Vonk Annelotte M. , Reggiori Fulvio , Rottier Peter J. M. , de Haan Cornelis A. M.
Published: February 2011

Green fluorescent protein (GFP)-tagged mouse hepatitis coronavirus nonstructural protein 4 (nsp4) was shown to localize to the endoplasmic reticulum (ER) and to be recruited to the coronavirus replicative structures. Fluorescence loss in photobleaching and fluorescence recovery after photobleaching experiments demonstrated that while the membranes of the ER are continuous with those harboring the replicative structures, the mobility of nsp4 at the latter structures is relatively restricted. In agreement with that observation, nsp4 was shown to be engaged in homotypic and heterotypic interactions, the latter with nsp3 and nsp6. In addition, the coexpression of nsp4 with nsp3 affected the subcellular localization of the two proteins.
Design of Chimeric Alphaviruses with a Programmed, Attenuated, Cell Type-Restricted Phenotype
Authors: Kim Dal Young , Atasheva Svetlana , Foy Niall J. , Wang Eryu , Frolova Elena I. , Weaver Scott , Frolov Ilya
Published: February 2011

The
Alphavirus
genus in the
Togaviridae
family contains a number of human and animal pathogens. The importance of alphaviruses has been strongly underappreciated; however, epidemics of chikungunya virus (CHIKV), causing millions of cases of severe and often persistent arthritis in the Indian subcontinent, have raised their profile in recent years. In spite of a continuous public health threat, to date no licensed vaccines have been developed for alphavirus infections. In this study, we have applied an accumulated knowledge about the mechanism of alphavirus replication and protein function in virus-host interactions to introduce a new approach in designing attenuated alphaviruses. These variants were constructed from genes derived from different, geographically isolated viruses. The resulting viable variants encoded CHIKV envelope and, in contrast to naturally circulating viruses, lacked the important contributors to viral pathogenesis: genes encoding proteins functioning in inhibition of cellular transcription and downregulation of the cellular antiviral response. To make these viruses incapable of transmission by mosquito vectors and to differentially regulate expression of viral structural proteins, their replication was made dependent on the internal ribosome entry sites, derived from other positive-polarity RNA (RNA
+
) viruses. The rational design of the genomes was complemented by selection procedures, which adapted viruses to replication in tissue culture and produced variants which (i) demonstrated different levels of replication and production of the individual structural proteins, (ii) efficiently induced the antiviral response in infected cells, (iii) were incapable of replication in cells of mosquito origin, and (iv) efficiently replicated in Vero cells. This modular approach to genome design is applicable for the construction of other alphaviruses with a programmed, irreversibly attenuated phenotype.
HIV-1 Escape from the CCR5 Antagonist Maraviroc Associated with an Altered and Less-Efficient Mechanism of gp120-CCR5 Engagement That Attenuates Macrophage Tropism
Authors: Roche Michael , Jakobsen Martin R. , Sterjovski Jasminka , Ellett Anne , Posta Filippo , Lee Benhur , Jubb Becky , Westby Mike , Lewin Sharon R. , Ramsland Paul A. , Churchill Melissa J. , Gorry Paul R.
Published: February 2011

Maraviroc (MVC) inhibits the entry of human immunodeficiency virus type 1 (HIV-1) by binding to and modifying the conformation of the CCR5 extracellular loops (ECLs). Resistance to MVC results from alterations in the HIV-1 gp120 envelope glycoproteins (Env) enabling recognition of the drug-bound conformation of CCR5. To better understand the mechanisms underlying MVC resistance, we characterized the virus-cell interactions of gp120 from
in vitro
-generated MVC-resistant HIV-1 (MVC-Res Env), comparing them with those of gp120 from the sensitive parental virus (MVC-Sens Env). In the absence of the drug, MVC-Res Env maintains a highly efficient interaction with CCR5, similar to that of MVC-Sens Env, and displays a relatively modest increase in dependence on the CCR5 N terminus. However, in the presence of the drug, MVC-Res Env interacts much less efficiently with CCR5 and becomes critically dependent on the CCR5 N terminus and on positively charged elements of the drug-modified CCR5 ECL1 and ECL2 regions (His88 and His181, respectively). Structural analysis suggests that the Val323 resistance mutation in the gp120 V3 loop alters the secondary structure of the V3 loop and the buried surface area of the V3 loop–CCR5 N terminus interface. This altered mechanism of gp120-CCR5 engagement dramatically attenuates the entry of HIV-1 into monocyte-derived macrophages (MDM), cell-cell fusion activity in MDM, and viral replication capacity in MDM. In addition to confirming that HIV-1 escapes MVC by becoming heavily dependent on the CCR5 N terminus, our results reveal novel interactions with the drug-modified ECLs that are critical for the utilization of CCR5 by MVC-Res Env and provide additional insights into virus-cell interactions that modulate macrophage tropism.
Cytomegalovirus UL103 Controls Virion and Dense Body Egress
Authors: Ahlqvist Jenny , Mocarski Edward
Published: February 2011

Human cytomegalovirus UL103 encodes a tegument protein that is conserved across herpesvirus subgroups. Mutant viruses lacking this gene product exhibit dramatically reduced accumulation of cell-free virus progeny and poor cell-to-cell spread. Given that viral proteins and viral DNA accumulate with normal kinetics in cells infected with mutant virus, UL103 appears to function during the late phase of replication, playing a critical role in egress of capsidless dense bodies and virions. Few dense bodies were observed in the extracellular space in mutant virus-infected cells in the presence or absence of the DNA encapsidation inhibitor 2-bromo-5,6-dichloro-1-(β-
d
-ribofuranosyl)benzimidazole. Upon reversal of encapsidation inhibition, UL103 had a striking impact on accumulation of cell-free virus, but not on accumulation of cell-associated virus. Thus, UL103 plays a novel and important role during maturation, regulating virus particle and dense body egress from infected cells.
A 128-Base-Pair Sequence Containing the
pac1
and a Presumed Cryptic
pac2
Sequence Includes
cis
Elements Sufficient To Mediate Efficient Genome Maturation of Human Cytomegalovirus
Authors: Wang Jian Ben , McVoy Michael A.
Published: February 2011

Herpesvirus DNA replication proceeds via concatemeric replicative intermediates that are comprised of head-to-tail linked genomes. Genome maturation is carried out by the terminase, an enzyme complex that mediates both the insertion of concatemer DNA into capsids and its subsequent cleavage to release genomes within these capsids. This cleavage is sequence specific, but the governing
cis
-acting DNA sequences are only partially characterized. Two highly conserved motifs, the
pac1
and
pac2
motifs, lie near the ends of herpesvirus genomes and are known to be critical for genome maturation. In murine cytomegalovirus, poorly conserved sequences distal to the
pac2
motif up to 150 bp from the point of cleavage are also important for cleavage. Here, we sought to identify the cleavage/packaging signals of human cytomegalovirus. Our results show that a previously proposed
pac2
-like poly(A) tract is dispensable for cleavage/packaging function and suggest that human cytomegalovirus may utilize a cryptic
pac2
motif that lacks a poly(A) tract characteristic of
pac2
motifs in other herpesviruses. Additional distal sequences 47 to 100 bp from the point of cleavage were found to enhance cleavage efficiency. These results should facilitate the identification of
trans
-acting factors that bind to these
cis
elements and elucidation of their functions. Such information will be critical for understanding the molecular basis of this complex process.
Adenovirus Core Protein VII Protects the Viral Genome from a DNA Damage Response at Early Times after Infection
Authors: Karen Kasey A. , Hearing Patrick
Published: February 2011

Adenovirus has a linear, double-stranded DNA genome that is perceived by the cellular Mre11-Rad50-Nbs1 (MRN) DNA repair complex as a double-strand break. If unabated, MRN elicits a double-strand break repair response that blocks viral DNA replication and ligates the viral genomes into concatemers. There are two sets of early viral proteins that inhibit the MRN complex. The E1B-55K/E4-ORF6 complex recruits an E3 ubiquitin ligase and targets MRN proteins for proteasome-dependent degradation. The E4-ORF3 protein inhibits MRN through sequestration. The mechanism that prevents MRN recognition of the viral genome prior to the expression of these early proteins was previously unknown. Here we show a temporal correlation between the loss of viral core protein VII from the adenovirus genome and a gain of checkpoint signaling due to the double-strand break repair response. While checkpoint signaling corresponds to the recognition of the viral genome, core protein VII binding to and checkpoint signaling at viral genomes are largely mutually exclusive. Transcription is known to release protein VII from the genome, and the inhibition of transcription shows a decrease in checkpoint signaling. Finally, we show that the nuclease activity of Mre11 is dispensable for the inhibition of viral DNA replication during a DNA damage response. These results support a model involving the protection of the incoming viral genome from checkpoint signaling by core protein VII and suggest that the induction of an MRN-dependent DNA damage response may inhibit adenovirus replication by physically masking the origins of DNA replication rather than altering their integrity.
Insights into Polyomaviridae MicroRNA Function Derived from Study of the Bandicoot Papillomatosis Carcinomatosis Viruses
Authors: Chen Chun Jung , Kincaid Rodney P. , Seo Gil Ju , Bennett Mark D. , Sullivan Christopher S.
Published: February 2011

Several different members of the
Polyomaviridae
, including some human pathogens, encode microRNAs (miRNAs) that lie antisense with respect to the early gene products, the tumor (T) antigens. These miRNAs negatively regulate T antigen expression by directing small interfering RNA (siRNA)-like cleavage of the early transcripts. miRNA mutant viruses of some members of the
Polyomaviridae
express increased levels of early proteins during lytic infection. However, the importance of miRNA-mediated negative regulation of the T antigens remains uncertain. Bandicoot papillomatosis carcinomatosis virus type 1 (BPCV1) is associated with papillomas and carcinomas in the endangered marsupial the western barred bandicoot (
Perameles bougainville
). BPCV1 is the founding member of a new group of viruses that remarkably share distinct properties in common with both the polyomavirus and papillomavirus families. Here, we show that BPCV1 encodes, in the same orientation as the papillomavirus-like transcripts, a miRNA located within a long noncoding region (NCR) of the genome. Furthermore, this NCR serves the function of both promoter and template for the primary transcript that gives rise to the miRNA. Unlike the polyomavirus miRNAs, the BPCV1 miRNA is not encoded antisense to the T antigen transcripts but rather lies in a separate, proximal region of the genome. We have mapped the 3′ untranslated region (UTR) of the BPCV1 large T antigen early transcript and identified a functional miRNA target site that is imperfectly complementary to the BPCV1 miRNA. Chimeric reporters containing the entire BPCV1 T antigen 3′ UTR undergo negative regulation when coexpressed with the BPCV1 miRNA. Notably, the degree of negative regulation observed is equivalent to that of an identical reporter that is engineered to bind to the BPCV1 miRNA with perfect complementarity. We also show that this miRNA and this novel mode of early gene regulation are conserved with the related BPCV2. Finally, papillomatous lesions from a western barred bandicoot express readily detectable levels of this miRNA, stressing its likely importance
in vivo
. Combined, the alternative mechanisms of negative regulation of T antigen expression between the BPCVs and the polyomaviruses support the importance of miRNA-mediated autoregulation in the life cycles of some divergent polyomaviruses and polyomavirus-like viruses.
Role of CCL-2, CCR-2 and CCR-4 in cerulein-induced acute pancreatitis and pancreatitis-associated lung injury
Authors: Frossard Jean Louis , Lenglet Sébastien , Montecucco Fabrizio , Steffens Sabine , Galan Katia , Pelli Graziano , Spahr Laurent , Mach Francois , Hadengue Antoine
Published: February 2011

Background and aims

Acute pancreatitis is an inflammatory process of variable severity. Leucocytes are thought to play a key role in the development of pancreatitis and pancreatitis-associated lung injury. The interactions between inflammatory cells and their mediators are crucial for determining tissue damage. Monocyte chemoattractant protein-1 (or CCL-2), CCR-2 and CCR-4 are chemokines and chemokine receptors involved in leucocyte trafficking. The aim of the study was to evaluate the role of the CCL-2, CCR-2 and CCR-4 chemokine receptors in the pathogenesis of cerulein-induced pancreatitis and pancreatitis-associated lung injury. To address the role of CCL-2, CCR-2 and CCR-4 that attracts leucocytes cells in inflamed tissues, pancreatitis was induced by administering supramaximal doses of cerulein in mice that do not express CCL-2, CCR-2 or CCR-4.

Methods

The severity of pancreatitis was measured by serum amylase, pancreatic oedema and acinar cell necrosis. Lung injury was quantitated by evaluating lung microvascular permeability and lung myeloperoxidase activity. Chemokine and chemokine-receptor expression were quantitated by real-time PCR. The nature of inflammatory cells invading the pancreas and lungs was studied by immunostaining.

Results

The authors have found that pancreas CCL-2 and CCR-2 levels rise during pancreatitis. Both pancreatitis and the associated lung injury are blunted, but not completely prevented, in mice deficient in CCL-2, whereas the deficiency in either CCR-2 or CCR-4 does not reduce the severity of both the pancreatitis and the lung injury. The amounts of neutrophils and monocyte/macrophages (MOMA)-2 cells were significantly lower in mice deficient in CCL-2 compared with their sufficient littermates.

Conclusions

These results suggest that CCL-2 plays a key role in pancreatitis by modulating the infiltration by neutrophils and MOMA-2 cells, and that its deficiency may improve the outcome of the disease.
CHAMELEON COSMOLOGY MODEL DESCRIBING THE PHANTOM DIVIDE LINE CROSSING
Authors: CANNATA FRANCESCO , KAMENSHCHIK ALEXANDER Y.
Published: February 2011

An exact solution describing the evolution of the type Bang-to-Rip with the phantom divide line crossing is constructed in the chameleon cosmology model, based on two independent functions of the scalar field.
SOLUTION OF SIMPLE PURSUIT-EVASION PROBLEM WHEN EVADER MOVES ON A GIVEN CURVE
Authors: KUCHKAROV ATAMURAT SH.
Published: February 2011

We investigate a simple motion pursuit-evasion differential game of one Pursuer and one Evader. Maximal speeds of the players are equal. The Evader moves along a given curve without self-intersection. There is no phase constraint for the Pursuer. Necessary and sufficient conditions to complete pursuit from both fixed initial position and all initial positions are obtained.
COALITIONAL SOLUTION OF A GAME-THEORETIC EMISSION REDUCTION MODEL
Authors: KOZLOVSKAYA NADEZHDA , PETROSYAN LEON , ZENKEVICH NIKOLAY
Published: February 2011

In this paper the problem of allocation over time of total cost incurred by coalitions of countries in a coalitional game of pollution reduction is considered. The Nash equilibrium in the game played by coalitions is computed and then the value of each coalition is allocated according to some given mechanism between its members.
Neoproterozoic loess and limits to snowball Earth
Authors: Retallack Gregory J.
Published: February 2011

Neoproterozoic tillites overlain by limestones and dolostones (cap carbonates) have been interpreted as evidence of abrupt climate change from glaciers to tropical seas on the assumption that cap carbonates were marine. This assumption is here challenged by evidence for loess deposition of the Nuccaleena Formation of South Australia from granulometry (angular, randomly oriented, silt, modal diameter 7ϕ) and sedimentary structures (climbing-translatent cross-stratification, linear dunes). In addition, a variety of palaeosols in the Nuccaleena Formation have red clayey horizons, replacive micritization, expansion cracks, and thufur mounds, as well as low carbon and oxygen isotope values, high strontium isotope ratios, and geochemical evidence of leaching and clay formation. This cap carbonate has no definitively marine features, and is here interpreted as periglacial loess overlying the fluvioglacial–intertidal Elatina Formation, so it is not a record of abrupt global warming from snowball Earth. Other cap carbonates around the world differ in various ways, and may have formed in different depositional environments, but could profitably be reconsidered from the new perspective of the loess depositional model proposed here.

Supplementary material:

Tabular comparison of marine and non-marine interpretations of cap carbonates, petrographic textures and composition, and new isotopic and chemical analyses of Nuccaleena Formation are available at
http:/www.geolsoc.org.uk/SUP18443
.
The amino acid transporter SNAT2 mediates l-proline-induced differentiation of ES cells
Authors: Tan Boon Siang Nicholas , Lonic Ana , Morris Michael B. , Rathjen Peter D. , Rathjen Joy
Published: February 2011

There is an increasing appreciation that amino acids can act as signaling molecules in the regulation of cellular processes through modulation of intracellular cell signaling pathways. In culture, embryonic stem (ES) cells can be differentiated to a second, pluripotent cell population, early primitive ectoderm-like cells in response to biological activities within the conditioned medium MEDII. The amino acid l-proline has been identified as a component of MEDII required for ES cell differentiation. Here, we define the primary l-proline transporter on ES and early primitive ectoderm-like cells as sodium-coupled neutral amino acid transporter 2 (SNAT2). SNAT2 uptake of l-proline can be inhibited by the addition of millimolar concentrations of other substrates. The addition of excess amino acids was used to regulate the uptake of l-proline by ES cells, and the effect on differentiation was analyzed. The ability of SNAT2 substrates, but not other amino acids, to prevent changes in morphology, gene expression, and differentiation kinetics suggested that l-proline uptake through SNAT2 was required for ES cell differentiation. These data reveal an unexpected role for amino acid uptake and the amino acid transporter SNAT2 in regulation of pluripotent cells in culture and provides a number of specific, inexpensive, and nontoxic culture additives with the potential to improve the quality of ES cell culture.
STAT1-mediated signal integration between IFNγ and LPS leads to increased EC and SMC activation and monocyte adhesion
Authors: Sikorski Krzysztof , Chmielewski Stefan , Przybyl Lukasz , Heemann Uwe , Wesoly Joanna , Baumann Marcus , Bluyssen Hans A. R.
Published: February 2011

Inflammation plays an important role in host defenses against infectious agents and injury, but it also contributes to the pathophysiology of atherosclerosis. Signal transducer and activated transcription 1 (STAT1) has been identified as a point of convergence for the cross talk between the pro-inflammatory cytokine interferon γ (IFNγ) and the Toll-like receptor-4 (TLR4) ligand LPS in immune cells. However, there is no information available on the role of STAT1 in TLR4-mediated progression of atherosclerosis and on potential synergism between lipopolysaccharides (LPS) and IFNγ signaling in cells from the vasculature. Cultured human microvascular endothelial cells (HMECs) exposed to LPS activated STAT1 in a delayed manner that was inhibited by cycloheximide treatment. Pretreatment of HMECs as well as primary vascular smooth muscle cells (VSMCs) with IFNγ followed by LPS resulted in a significant increase in STAT1 phosphorylation compared with both factors alone. Increased STAT1 protein levels, strictly mediated by IFNγ, correlated with the augmented STAT1 phosphorylation that was absent in TLR4−/− cells. As assessed by PCR, Western analysis, and ELISA, this coincided with increased expression of the chemokine interferon gamma-induced protein 10 kDa (IP-10) and the adhesion molecule ICAM-1 in a TLR4-dependent manner.The STAT1-inhibitor fludarabine markedly reduced these effects as well as IFNγ and LPS-dependent adhesion of U937 cells to endothelial cells, emphasizing the potential importance of STAT1 in the integration of both signals. With the established roles of IFNγ and TLRs in atherosclerotic pathology, the STAT1-dependent signal integration between IFNγ and TLR in ECs and VSMCs in response to exogenous and endogenous atherogenic ligands could result in amplification of pro-inflammatory responses in the damaged vessel and be a novel mechanism involved in the initiation and progression of atherosclerosis.
Obesity, diabetes mellitus, and liver fibrosis
Authors: Chiang Dian J. , Pritchard Michele T. , Nagy Laura E.
Published: February 2011

Obesity is a global epidemic with more than 1 billion overweight adults and at least 300 million obese patients worldwide. Diabetes is characterized by a defect in insulin secretion or a decrease in sensitivity to insulin, which results in elevated fasting blood glucose. Both obesity and elevated fasting glucose are risk factors for nonalcoholic fatty liver disease, a disease spectrum that includes hepatic steatosis (nonalcoholic fatty liver), nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. Increased adiposity and insulin resistance contribute to the progression from NASH to fibrosis through the development of a profibrotic mileau in the liver, including increased hepatocellular death, increased reactive oxygen species generation, and an altered adipokine/cytokine balance. This review will summarize recent advances in our understanding of the pathological interactions among excessive fat accumulation, insulin resistance, and hepatic fibrogenesis and discuss specific molecular pathways that may be of interest in the development of therapeutic interventions to prevent and/or reverse hepatic fibrosis.
Luminal flow regulates NO and O2−along the nephron
Authors: Cabral Pablo D. , Garvin Jeffrey L.
Published: February 2011

Urinary flow is not constant but in fact highly variable, altering the mechanical forces (shear stress, stretch, and pressure) exerted on the epithelial cells of the nephron as well as solute delivery. Nitric oxide (NO) and superoxide (O2−) play important roles in various processes within the kidney. Reductions in NO and increases in O2−lead to abnormal NaCl and water absorption and hypertension. In the last few years, luminal flow has been shown to be a regulator of NO and O2−production along the nephron. Increases in luminal flow enhance fluid, Na, and bicarbonate transport in the proximal tubule. However, we know of no reports directly addressing flow regulation of NO and O2−in this segment. In the thick ascending limb, flow-stimulated NO and O2−formation has been extensively studied. Luminal flow stimulates NO production by nitric oxide synthase type 3 and its translocation to the apical membrane in medullary thick ascending limbs. These effects are mediated by flow-induced shear stress. In contrast, flow-induced stretch and NaCl delivery stimulate O2−production by NADPH oxidase in this segment. The interaction between flow-induced NO and O2−is complex and involves more than one simply scavenging the other. Flow-induced NO prevents flow from increasing O2−production via cGMP-dependent protein kinase in thick ascending limbs. In macula densa cells, shear stress increases NO production and this requires that the primary cilia be intact. The role of luminal flow in NO and O2−production in the distal tubule is not known. In cultured inner medullary collecting duct cells, shear stress enhances nitrite accumulation, a measure of NO production. Although much progress has been made on this subject in the last few years, there are still many unanswered questions.
Pharmacology of currents underlying the different firing patterns of spinal sensory neurons and interneurons identified in vivo using multivariate analysis
Authors: Winlove Crawford I. P. , Roberts Alan
Published: February 2011

The operation of neuronal networks depends on the firing patterns of the network's neurons. When sustained current is injected, some neurons in the central nervous system fire a single action potential and others fire repetitively. For example, in Xenopus laevis tadpoles, primary-sensory Rohon-Beard (RB) neurons fired a single action potential in response to 300-ms rheobase current injections, whereas dorsolateral (DL) interneurons fired repetitively at 10–20 Hz. To investigate the basis for these differences in vivo, we examined drug-induced changes in the firing patterns of Xenopus spinal neurons using whole cell current-clamp recordings. Neuron types were initially separated through cluster analysis, and we compared results produced using different clustering algorithms. We used these results to develop a predictive function to classify subsequently recorded neurons. The potassium channel blocker tetraethylammonium (TEA) converted single-firing RB neurons to low-frequency repetitive firing but reduced the firing frequency of repetitive-firing DL interneurons. Firing frequency in DL interneurons was also reduced by the potassium channel blockers 4-aminopyridine (4-AP), catechol, and margatoxin; 4-AP had the greatest effect. The calcium channel blockers amiloride and nimodipine had few effects on firing in either neuron type but reduced action potential duration in DL interneurons. Muscarine, which blocks M-currents, did not affect RB neurons but reduced firing frequency in DL interneurons. These results suggest that potassium currents may control neuron firing patterns: a TEA-sensitive current prevents repetitive firing in RB neurons, whereas a 4-AP-sensitive current underlies repetitive firing in DL interneurons. The cluster and discriminant analysis described could help to classify neurons in other systems.
Eyeblink conditioning contingent on hippocampal theta enhances hippocampal and medial prefrontal responses
Authors: Darling Ryan D. , Takatsuki Kanako , Griffin Amy L. , Berry Stephen D.
Published: February 2011

Trace eyeblink classical conditioning (tEBCC) can be accelerated by making training trials contingent on the naturally generated hippocampal 3- to 7-Hz theta rhythm. However, it is not well-understood how the presence (or absence) of theta affects stimulus-driven changes within the hippocampus and how it correlates with patterns of neural activity in other essential trace conditioning structures, such as the medial prefrontal cortex (mPFC). In the present study, a brain-computer interface delivered paired or unpaired conditioning trials to rabbits during the explicit presence (T+) or absence (T−) of theta, yielding significantly faster behavioral learning in the T+-paired group. The stimulus-elicited hippocampal unit responses were larger and more rhythmic in the T+-paired group. This facilitation of unit responses was complemented by differences in the hippocampal local field potentials (LFP), with the T+-paired group demonstrating more coherent stimulus-evoked theta than T−-paired animals and both unpaired groups. mPFC unit responses in the rapid learning T+-paired group displayed a clear inhibitory/excitatory sequential pattern of response to the tone that was not seen in any other group. Furthermore, sustained mPFC unit excitation continued through the trace interval in T+animals but not in T−animals. Thus theta-contingent training is accompanied by 1) acceleration in behavioral learning, 2) enhancement of the hippocampal unit and LFP responses, and 3) enhancement of mPFC unit responses. Together, these data provide evidence that pretrial hippocampal state is related to enhanced neural activity in critical structures of the distributed network supporting the acquisition of tEBCC.
Hsp70 and Its Molecular Role in Nervous System Diseases
Authors: Turturici Giuseppina , Sconzo Gabriella , Geraci Fabiana
Published: February 2011

Heat shock proteins (HSPs) are induced in response to many injuries including stroke, neurodegenerative disease, epilepsy, and trauma. The overexpression of one HSP in particular, Hsp70, serves a protective role in several different models of nervous system injury, but has also been linked to a deleterious role in some diseases. Hsp70 functions as a chaperone and protects neurons from protein aggregation and toxicity (Parkinson disease, Alzheimer disease, polyglutamine diseases, and amyotrophic lateral sclerosis), protects cells from apoptosis (Parkinson disease), is a stress marker (temporal lobe epilepsy), protects cells from inflammation (cerebral ischemic injury), has an adjuvant role in antigen presentation and is involved in the immune response in autoimmune disease (multiple sclerosis). The worldwide incidence of neurodegenerative diseases is high. As neurodegenerative diseases disproportionately affect older individuals, disease-related morbidity has increased along with the general increase in longevity. An understanding of the underlying mechanisms that lead to neurodegeneration is key to identifying methods of prevention and treatment. Investigators have observed protective effects of HSPs induced by preconditioning, overexpression, or drugs in a variety of models of brain disease. Experimental data suggest that manipulation of the cellular stress response may offer strategies to protect the brain during progression of neurodegenerative disease.
Aerodynamic Analysis of a Manned Space Vehicle for Missions to Mars
Authors: Pezzella Giuseppe , Viviani Antonio
Published: February 2011

The paper deals with the aerodynamic analysis of a manned braking system entering the Mars atmosphere with the aim to support planetary entry system design studies. The exploration vehicle is an axisymmetric blunt body close to the Apollo capsule. Several fully three‐dimensional computational fluid dynamics analyses have been performed to address the capsule aerodynamic performance. To this end, a wide range of flow conditions including reacting and nonreacting flow, different angles of attack, and Mach numbers have been investigated and compared. Moreover, nonequilibrium effects on the flow field around the entry vehicle have also been investigated. Results show that real‐gas effects, for all the angles of attack considered, increase both the aerodynamic drag and pitching moment whereas the lift is only slighted affected. Finally, results comparisons highlight that experimental and CFD aerodynamic findings available for the Apollo capsule in air adequately represent the static coefficients of the capsule in the Mars atmosphere.
Assessment of an Anomaly Detector for Jet Engine Health Monitoring
Authors: Borguet Sebastien , Léonard Olivier
Published: February 2011

The goal of module performance analysis is to reliably assess the health of the main components of an aircraft engine. A predictive maintenance strategy can leverage this information to increase operability and safety as well as to reduce costs. Degradation undergone by an engine can be divided into gradual deterioration and accidental events. Kalman filters have proven very efficient at tracking progressive deterioration but are poor performers in the face of abrupt events. Adaptive estimation is considered as an appropriate solution to this deficiency. This paper reports the evaluation of the detection capability of an adaptive diagnosis tool on the basis of simulated scenarios that may be encountered during the operation of a commercial turbofan engine. The diagnosis tool combines a Kalman filter and a secondary system that monitors the residuals. This auxiliary component implements a generalised likelihood ratio test in order to detect abrupt events.
A Gene Expression Signature from Human Breast Cancer Cells with Acquired Hormone Independence Identifies MYC as a Mediator of Antiestrogen Resistance
Authors: Miller Todd W. , Balko Justin M. , Ghazoui Zara , Dunbier Anita , Anderson Helen , Dowsett Mitch , González-Angulo Ana M. , Mills Gordon B. , Miller William R. , Wu Huiyun , Shyr Yu , Arteaga Carlos L.
Published: February 2011

Purpose: Although most patients with estrogen receptor α (ER)-positive breast cancer initially respond to endocrine therapy, many ultimately develop resistance to antiestrogens. However, mechanisms of antiestrogen resistance and biomarkers predictive of such resistance are underdeveloped.

Experimental Design: We adapted four ER+ human breast cancer cell lines to grow in an estrogen-depleted medium. A gene signature of estrogen independence was developed by comparing expression profiles of long-term estrogen-deprived (LTED) cells to their parental counterparts. We evaluated the ability of the LTED signature to predict tumor response to neoadjuvant therapy with an aromatase inhibitor and disease outcome following adjuvant tamoxifen. We utilized Gene Set Analysis (GSA) of LTED cell gene expression profiles and a loss-of-function approach to identify pathways causally associated with resistance to endocrine therapy.

Results: The LTED gene expression signature was predictive of high tumor cell proliferation following neoadjuvant therapy with anastrozole and letrozole, each in different patient cohorts. This signature was also predictive of poor recurrence-free survival in two studies of patients treated with adjuvant tamoxifen. Bioinformatic interrogation of expression profiles in LTED cells revealed a signature of MYC activation. The MYC activation signature and high MYC protein levels were both predictive of poor outcome following tamoxifen therapy. Finally, knockdown of MYC inhibited LTED cell growth.

Conclusions: A gene expression signature derived from ER+ breast cancer cells with acquired hormone independence predicted tumor response to aromatase inhibitors and associated with clinical markers of resistance to tamoxifen. Activation of the MYC pathway was associated with this resistance. Clin Cancer Res; 17(7); 2024–34. ©2011 AACR.
Initiating, Developing and Evaluating a Comprehensive Spinal Defects Clinic: A Clinical Report
Authors: Aldana Philipp R. , Wood David L. , Postlethwait Richard A. , James Hector E.
Published: February 2011

Objective: The Division of Pediatric Neurosurgery of the University of Florida College of Medicine – Jacksonville developed a multidisciplinary clinic for the better management of pediatric patients with spinal defects. The purpose of this report is to assist neurosurgeons in those regions and countries where there are no spinal defects clinics (SDC). Methods: We induced a staged process to develop a comprehensive multidisciplinary clinic for pediatric patients with spinal defects: phase I – during December 2003 to June 2004, the organizational planning, multiinstitutional recruitment of health care personnel and location of clinic space occurred; phase II – the SDC sessions initiated in June 2004 and have consequently been held on a monthly basis; phase III – this consisted of a quality improvement program during which parents/caregivers were surveyed. Results: Between June 2004 and February 2009, 139 patients/families were evaluated. Diagnoses included: myelomeningocele (102), lipomeningocele (18), meningocele (1), myelocystocele (3), spina bifida occulta (9), spinal trauma (2), spasticity of cerebral origin (2), spinal arachnoid cyst (1) and syringomyelia (1). During this period, 110 parents/caregivers were questioned on how the SDC assisted in the care of their child. A total of 62% (of 53 responders) indicated the SDC allowed them to be better informed about their child’s medical conditions and short/long-term health care plans, 52% stated health care needs were better coordinated than prior to their participation in the SDC, and 26% responded that the initiation of the clinic had reduced their medical care travel. Conclusions: Pediatric neurosurgeons may take the lead in organizing a multidisciplinary clinic for the betterment of these children. Multidisciplinary care settings facilitate health care delivery and lead to better patient care as perceived by parents/caregivers.
Mécanisme moléculaire de la phénylcétonurie: Du génotype à la prise en charge clinique
Authors: Zschocke Johannes
Published: February 2011

À l’heure du dépistage néonatal et du traitement pré-symptomatique des individus atteints de phénylcétonurie, cette maladie n’est plus caractérisée par un ensemble de symptômes observés chez des patients non traités: c’est à présent une prédisposition héréditaire qui nécessite un régime pour éviter des dommages cérébraux et des déficiences intellectuelles. L’analyse des relations entre génotype et phénotype doit donc permettre de définir la nature et les modalités d’un traitement préventif. En cas de phénylcétonurie, la détection des mutations n’est pas obligatoire pour réaliser un diagnostic correct et envisager un traitement, tel que l’administration de tétrahydrobioptérine (BH4). Cependant, l’impact fonctionnel des mutations individuelles a été largement analysé ces dernières années et il existe des corrélations bien définies entre le génotype et différents phénotypes. Connaître et comprendre le génotype très précocement permet souvent de prédire la sévérité du déficit en phénylalanine hydroxylase et d’envisager les caractéristiques de la maladie pour un individu. Cela peut également aider à la prise en charge clinique. L‘identification de l‘homozygotie ou de l‘hétérozygotie composite pour des mutations nulles indique que ce patient ne tirera aucun bénéfice d’un traitement par la BH4. En revanche, l’identification d’une mutation BH4-sensible chez un patient classé comme non répondant à la BH4 devrait conduire à reconsidérer la classification du patient et à refaire un essai de traitement avec la BH4. Des précautions doivent être prises pour détecter les éventuelles erreurs dans les résultats des études moléculaires et pour analyser ces erreurs à la lumière des données cliniques et biochimiques de l’individu.
Prise en charge nutritionnelle de la phénylcétonurie
Authors: MacLeod Erin L. , Ney Denise M.
Published: February 2011

La phénylcétonurie (PCU) est due à un déficit de l’activité de la phénylalanine hydroxylase, nécessaire pour métaboliser un acide aminé (AA) essentiel, la phénylalanine (Phe), en tyrosine. Afin de prévenir les atteintes neurologiques, il est recommandé de suivre un régime pauvre en Phe à vie, c’est-à-dire de limiter la consommation d’aliments naturels et de consommer une préparation à base d’AA, sans Phe, pour couvrir les besoins protéiques. L’objectif de la prise en charge nutritionnelle des patients phénylcétonuriques est de maintenir une concentration plasmatique en Phe compatible avec une croissance, un développement, et une activité mentale optimaux tout en apportant un régime nutritionnellement complet. Cet article présente la mise en place d’une prescription alimentaire à vie pour les patients phénylcétonuriques, les résultats de cette prise en charge nutritionnelle, la compliance avec le régime pauvre en Phe durant les différentes étapes de la vie, et les nouvelles possibilités de prise en charge. La prescription alimentaire doit être individualisée pour répondre aux besoins nutritionnels de chaque patient, et l’adéquation des apports en Phe doit être régulée en fonction de la phénylalaninémie, contrôlée régulièrement. La maladie, des apports excessifs ou inadéquats en Phe, ou une consommation inadaptée de préparation à base d’AA peuvent induire une augmentation de la concentration sanguine en Phe. Même si l’observance du régime pauvre en Phe permet une croissance et un développement normaux, il est important de contrôler les statuts en vitamines, minéraux et acides gras essentiels, surtout chez les patients ne consommant pas suffisamment de mélange d’AA. Avec une population croissante d’adultes phénylcétonuriques, des recherches supplémentaires sont nécessaires pour comprendre les risques de développement d’ostéoporose ou de maladies cardiovasculaires. De nouvelles possibilités permettant d’assouplir le régime et d’améliorer le contrôle métabolique sont prometteuses, comme un traitement à base de tetrahydrobioptérine ou une complémentation avec des AA neutres de grande taille. De plus, les aliments fabriqués avec le glycomacropeptide, une protéine intacte contenant très peu de Phe, améliorent le régime en offrant une alternative plus appétissante que les mélanges d’AA. En résumé, la poursuite des efforts est nécessaire pour surmonter le plus grand défi pour un patient phénylcétonurique: l’observance à vie d’un régime pauvre en Phe.
Altérations neuropsychologiques chez les patients phénylcétonuriques traités précocement: Revue
Authors: Crossley Louise H. , Anderson Peter J.
Published: February 2011

La phénylcétonurie (PCU) est une erreur innée du métabolisme causée par un déficit de l’activité de la phénylalanine hydroxylase, induisant une phénylalaninémie élevée et une tyrosinémie faible. Si cette maladie n’est pas traitée, elle engendre une neuropathologie sévère associée à des troubles neurocomportementaux. Le dépistage néonatal et la mise en place précoce d’un régime alimentaire réduisent significativement ces morbidités. Malgré un fonctionnement intellectuel général relativement bien préservé, un déficit cognitif léger et de faibles troubles comportementaux persistent chez les patients traités. Cet article présente les données sur les altérations du traitement de l’information, des fonctions exécutives, de la mémoire et l’apprentissage, de la réussite scolaire et du comportement. Il présente également les deux premières théories, le dysfonctionnement préfrontal et les anomalies de la substance blanche, proposées pour expliquer les mécanismes sous-jacents de ces déficits cognitifs et comportementaux observés chez les patients traités. Bien que des recherches supplémentaires soient nécessaires, la littérature actuelle suggère que les patients phénylcétonuriques traités précocement pourraient présenter des risques de troubles neurocomportementaux légers dans différents domaines neuropsychologiques. Ces patients doivent donc être examinés régulièrement de façon à pouvoir détecter ces troubles le plus tôt possible et ainsi pouvoir mettre en place des interventions adaptées permettant à ces patients d’atteindre leur potentiel optimal.
Role of Interpeduncular and Prepontine Cistern Cerebrospinal Fluid Flow Measurements in Prediction of Endoscopic Third Ventriculostomy Success in Pediatric Triventricular Hydrocephalus
Authors: Anik Ihsan , Etus Volkan , Anik Yonca , Ceylan Savas
Published: February 2011

Aim: The aim of the present study was to evaluate the correlation of the clinical success of the endoscopic third ventriculostomy (ETV) procedure with the measurements of cerebrospinal fluid (CSF) flow through the interpeduncular and prepontine cisterns in pediatric triventricular hydrocephalus. Methods: 51 children (age range: 25–201 months; mean: 55.3 months) with primary aqueductal stenosis who have been treated with ETV were included in the study. All patients were analyzed by conventional and cine magnetic resonance imaging (MRI) before and after endoscopic treatment. Both the stroke volume and the flow velocity of CSF in the interpeduncular and prepontine cisterns were evaluated. The MRI findings were correlated with clinical outcome. Simple descriptive and independent t tests were used for statistical analyses, and receiver operating characteristic curve analysis was used for the cutoff value of the ‘flow index’ (FI). Results: Among the 51 patients, 37 patients (72.5%) responded to ETV clinically during long-term follow-up. A further analysis was made for the prediction of who would respond to ETV, using the formula (stroke volume of prepontine cistern/stroke volume of interpeduncular cistern) ×100, which was defined as the FI. Early postoperative FI values of over 40% were significantly correlated with ETV success. Conclusion: Our results suggest that ETV success can be predicted by the ratio of early CSF stroke volume values of the interpeduncular and prepontine cisterns.
Expression of ACE and ACE2 in Patients with Hypertensive Nephrosclerosis
Authors: Wang Gang , Lai Fernand Mac-Moune , Kwan Bonnie C.H. , Lai Ka-Bik , Chow Kai-Ming , Li Philip K.T. , Szeto Cheuk-Chun
Published: February 2011

Background: The interplay between intrarenal angiotensin-converting enzyme (ACE) and type 2 ACE (ACE2) might play important roles in the pathogenesis of hypertensive nephrosclerosis (HTN), but human data are limited. Methods: Renal biopsy specimens of 41 patients with HTN and 10 transplant donors as controls (CTL) were studied. The glomerular and tubulointerstitial mRNA expression of ACE and ACE2 was measured by laser microdissection and real-time quantitative polymerase chain reaction. The corresponding protein level was determined by immunohistochemistry. Results: Neither the glomerular nor tubulointerstitial mRNA expression of ACE or ACE2 correlated with the corresponding protein level by immunohistochemistry. The tubulointerstitial levels of ACE and ACE2 were significantly lower in HTN than CTL, while the glomerular ACE and ACE2 levels were similar between the groups. The tubulointersitial ACE and ACE2 levels significantly correlated with the estimated glomerular filtration rate (GFR) and inversely with the degree of histological damage. The glomerular ACE and ACE2 levels significantly correlated with the rate of GFR decline. The ratio of glomerular ACE and ACE2 level correlated with the estimated GFR and the degree of glomerulosclerosis. Conclusion: Our results suggest that intrarenal ACE and ACE2 may play an important role in the pathogenesis and progression of HTN. Studies based on the mRNA expression of ACE and ACE2 should be cautiously interpreted.