bluuebunny/crossref_metadata_2025 huggingface dataset:
Genomic imbalances in patients with a clinical presentation in the spectrum of Cornelia de Lange syndrome
Authors: Gervasini Cristina , Picinelli Chiara , Azzollini Jacopo , Rusconi Daniela , Masciadri Maura , Cereda Anna , Marzocchi Cinzia , Zampino Giuseppe , Selicorni Angelo , Tenconi Romano , Russo Silvia , Larizza Lidia , Finelli Palma
Published: April 2013

Background

Cornelia de Lange syndrome (CdLS) is a rare autosomal-dominant disorder characterised by facial dysmorphism, growth and psychomotor developmental delay and skeletal defects. To date, causative mutations in the NIPBL (cohesin regulator) and SMC1A (cohesin structural subunit) genes account for > 50% and 6% of cases, respectively.

Methods

We recruited 50 patients with a CdLS clinical diagnosis or with features that overlap with CdLS, who were negative for mutations at NIPBL and SMC1A at molecular screening. Chromosomal rearrangements accounting for the clinical diagnosis were screened for using array Comparative Genomic Hybridisation (aCGH).

Results

Four patients were shown to carry imbalances considered to be candidates for having pathogenic roles in their clinical phenotypes: patient 1 had a 4.2 Mb de novo deletion at chromosome 20q11.2-q12; patient 2 had a 4.8 Mb deletion at chromosome 1p36.23-36.22; patient 3 carried an unbalanced translocation, t(7;17), with a 14 Mb duplication of chromosome 17q24.2-25.3 and a 769 Kb deletion at chromosome 7p22.3; patient 4 had an 880 Kb duplication of chromosome 19p13.3, for which his mother, who had a mild phenotype, was also shown to be a mosaic.

Conclusions

Notwithstanding the variability in size and gene content of the rearrangements comprising the four different imbalances, they all map to regions containing genes encoding factors involved in cell cycle progression or genome stability. These functional similarities, also exhibited by the known CdLS genes, may explain the phenotypic overlap between the patients included in this study and CdLS. Our findings point to the complexity of the clinical diagnosis of CdLS and confirm the existence of phenocopies, caused by imbalances affecting multiple genomic regions, comprising 8% of patients included in this study, who did not have mutations at NIPBL and SMC1A. Our results suggests that analysis by aCGH should be recommended for CdLS spectrum cases with an unexplained clinical phenotype and included in the flow chart for diagnosis of cases with a clinical evaluation in the CdLS spectrum.
Dynamical behaviors of a discrete SIS epidemic model with standard incidence and stage structure
Authors: Teng Zhidong , Nie Linfei , Xu Jiabo
Published: April 2013

A discrete SIS epidemic model with stage structure and standard incident rate which is governed by Beverton-Holt type is studied. The sufficient conditions on the permanence and extinction of disease are established. The existence of the endemic equilibrium is obtained. Further, by using the method of linearization, the local asymptotical stability of the endemic equilibrium is also studied. Lastly, the examples and numerical simulations carried out to illustrate the feasibility of the main results and revealed the far richer dynamical behaviors of the discrete epidemic model compared with the corresponding continuous epidemic models.

MSC:39A30, 92D30.
Limited cross-border infections in patients newly diagnosed with HIV in Europe
Authors: Frentz Dineke , Wensing Annemarie M J , Albert Jan , Paraskevis Dimitrios , Abecasis Ana B , Hamouda Osamah , Jørgensen Louise B , Kücherer Claudia , Struck Daniel , Schmit Jean-Claude , Åsjö Birgitta , Balotta Claudia , Beshkov Danail , Camacho Ricardo J , Clotet Bonaventura , Coughlan Suzie , De Wit Stéphane , Griskevicius Algirdas , Grossman Zehava , Horban Andrzej , Kolupajeva Tatjana , Korn Klaus , Kostrikis Leondios G , Liitsola Kirsi , Linka Marek , Nielsen Claus , Otelea Dan , Paredes Roger , Poljak Mario , Puchhammer-Stöckl Elisabeth , Sönnerborg Anders , Stanekova Danica , Stanojevic Maja , Vandamme Anne-Mieke , Boucher Charles A B , Van de Vijver David A M C ,   SPREAD Programme
Published: April 2013

Background

International travel plays a role in the spread of HIV-1 across Europe. It is, however, not known whether international travel is more important for spread of the epidemic as compared to endogenous infections within single countries. In this study, phylogenetic associations among HIV of newly diagnosed patients were determined across Europe.

Results

Data came from the SPREAD programme which collects samples of newly diagnosed patients that are representative for national HIV epidemics. 4260 pol sequences from 25 European countries and Israel collected in 2002–2007 were included.

We identified 457 clusters including 1330 persons (31.2% of all patients). The cluster size ranged between 2 and 28. A number of 987 patients (74.2%) were part of a cluster that consisted only of patients originating from the same country. In addition, 135 patients (10.2%) were in a cluster including only individuals from neighboring countries. Finally, 208 patients (15.6%) clustered with individuals from countries without a common border. Clustering with patients from the same country was less prevalent in patients being infected with B subtype (P-value <0.0001), in men who have sex with men (P-value <0.0001), and in recently infected patients (P-value =0.045).

Conclusions

Our findings indicate that the transmission of HIV-1 in Europe is predominantly occurring between patients from the same country. This could have implications for HIV-1 transmission prevention programmes. Because infections through travelling between countries is not frequently observed it is important to have good surveillance of the national HIV-1 epidemics.
Genome-scale analyses of butanol tolerance in Saccharomyces cerevisiae reveal an essential role of protein degradation
Authors: González-Ramos Daniel , van den Broek Marcel , van Maris Antonius JA , Pronk Jack T , Daran Jean-Marc G
Published: April 2013

Background

n-Butanol and isobutanol produced from biomass-derived sugars are promising renewable transport fuels and solvents. Saccharomyces cerevisiae has been engineered for butanol production, but its high butanol sensitivity poses an upper limit to product titers that can be reached by further pathway engineering. A better understanding of the molecular basis of butanol stress and tolerance of S. cerevisiae is important for achieving improved tolerance.

Results

By combining a screening of the haploid S. cerevisiae knock-out library, gene overexpression, and genome analysis of evolutionary engineered n-butanol-tolerant strains, we established that protein degradation plays an essential role in tolerance. Strains deleted in genes involved in the ubiquitin-proteasome system and in vacuolar degradation of damaged proteins showed hypersensitivity to n- butanol. Overexpression of YLR224W, encoding the subunit responsible for the recognition of damaged proteins of an ubiquitin ligase complex, resulted in a strain with a higher n-butanol tolerance. Two independently evolved n-butanol-tolerant strains carried different mutations in both RPN4 and RTG1, which encode transcription factors involved in the expression of proteasome and peroxisomal genes, respectively. Introduction of these mutated alleles in the reference strain increased butanol tolerance, confirming their relevance in the higher tolerance phenotype. The evolved strains, in addition to n-butanol, were also more tolerant to 2-butanol, isobutanol and 1-propanol, indicating a common molecular basis for sensitivity and tolerance to C3 and C4 alcohols.

Conclusions

This study shows that maintenance of protein integrity plays an essential role in butanol tolerance and demonstrates new promising targets to engineer S. cerevisiae for improved tolerance.
The pea aphid uses a version of the terminal system during oviparous, but not viviparous, development
Authors: Bickel Ryan D , Cleveland Hillary C , Barkas Joanna , Jeschke Caitlin C , Raz Amelie A , Stern David L , Davis Gregory K
Published: April 2013

Background

In most species of aphid, female nymphs develop into either sexual or asexual adults depending on the length of the photoperiod to which their mothers were exposed. The progeny of these sexual and asexual females, in turn, develop in dramatically different ways. The fertilized oocytes of sexual females begin embryogenesis after being deposited on leaves (oviparous development) while the oocytes of asexual females complete embryogenesis within the mother (viviparous development). Compared with oviparous development, viviparous development involves a smaller transient oocyte surrounded by fewer somatic epithelial cells and a smaller early embryo that comprises fewer cells. To investigate whether patterning mechanisms differ between the earliest stages of the oviparous and viviparous modes of pea aphid development, we examined the expression of pea aphid orthologs of genes known to specify embryonic termini in other insects.

Results

Here we show that pea aphid oviparous ovaries express torso-like in somatic posterior follicle cells and activate ERK MAP kinase at the posterior of the oocyte. In addition to suggesting that some posterior features of the terminal system are evolutionarily conserved, our detection of activated ERK in the oocyte, rather than in the embryo, suggests that pea aphids may transduce the terminal signal using a mechanism distinct from the one used in Drosophila. In contrast with oviparous development, the pea aphid version of the terminal system does not appear to be used during viviparous development, since we did not detect expression of torso-like in the somatic epithelial cells that surround either the oocyte or the blastoderm embryo and we did not observe restricted activated ERK in the oocyte.

Conclusions

We suggest that while oviparous oocytes and embryos may specify posterior fate through an aphid terminal system, viviparous oocytes and embryos employ a different mechanism, perhaps one that does not rely on an interaction between the oocyte and surrounding somatic cells. Together, these observations provide a striking example of a difference in the fundamental events of early development that is both environmentally induced and encoded by the same genome.
Classification of Hungarian medieval silver coins using x-ray fluorescent spectroscopy and multivariate data analysis
Authors: Rácz Anita , Héberger Károly , Rajkó Róbert , Elek János
Published: April 2013

Background

A set of silver coins from the collection of Déri Museum Debrecen (Hungary) was examined by X-ray fluorescent elemental analysis with the aim to assign the coins to different groups with the best possible precision based on the acquired chemical information and to build models, which arrange the coins according to their historical periods.

Results

Principal component analysis, linear discriminant analysis, partial least squares discriminant analysis, classification and regression trees and multivariate curve resolution with alternating least squares were applied to reveal dominant pattern in the data and classify the coins into several groups. We also identified those chemical components, which are present in small percentages, but are useful for the classification of the coins. With the coins divided into two groups according to adequate historical periods, we have obtained a correct classification (76-78%) based on the chemical compositions.

Conclusions

X-ray fluorescent elemental analysis together with multivariate data analysis methods is suitable to group medieval coins according to historical periods.
Analytical pyrolysis with in-situ silylation, Py(HMDS)-GC/MS, for the chemical characterization of archaeological and historical amber objects
Authors: Colombini Maria Perla , Ribechini Erika , Rocchi Marco , Selleri Paola
Published: April 2013

Introduction

An optimised analytical technique based on pyrolysis coupled with gas chromatography/mass spectrometry (Py-GC/MS) and derivatisation in situ with hexamethyldisilazane (HMDS) was used to study several archaeological and artistic amber objects. The aim was to verify the authenticity of the objects and to provide historical information regarding the geographical origin of the ambers, and thus reveal the trade routes between different ancient civilizations.

Results

Py-GC/MS using HMDS as a silylating agent enabled us not only to identify the geographical origin of the archaeological and artistic ambers as succinites, but also highlighted the degradation of amber objects revealing a lower abundance of free diterpenes on the surface.

Conclusion

This work demonstrates the capability of Py-GC/MS with silylation in situ to identify the geographical origin of archaeological ambers and to provide crucial information regarding their degradation process. The porous and rough appearance of the outer layer can be correlated with the higher lixiviation and to the evaporation of free diterpenes from the surface. The knowledge of the amber degradation mechanisms is crucial to select proper conservation-restoration methods.
Influence of Time to Change's social marketing interventions on stigma in England 2009-2011
Authors: Evans-Lacko Sara , Malcolm Estelle , West Keon , Rose Diana , London Jillian , Rüsch Nicolas , Little Kirsty , Henderson Claire , Thornicroft Graham
Published: April 2013

Background

England's Time To Change (TTC) social marketing campaign emphasised social contact between people with and without mental health problems to reduce stigma and discrimination.

Aims

We aimed to assess the effectiveness of the mass media component and also that of the mass social contact events.

Method

Online interviews were performed before and after each burst of mass media social marketing to evaluate changes in knowledge, attitudes and behaviour and associations between campaign awareness and outcomes. Participants at social contact events were asked about the occurrence and quality of contact, attitudes, readiness to discuss mental health and intended behaviour towards people with mental health problems.

Results

Prompted campaign awareness was 38-64%. A longitudinal improvement was noted for one intended behaviour item but not for knowledge or attitudes. Campaign awareness was positively associated with greater knowledge (β = 0.80, 95% CI 0.52-1.08) and more favourable attitudes (commonality OR 1.37, 95% CI 1.10-1.70; dangerousness OR 1.41, 95% CI 1.22-1.63) and intended behaviour (β = 0.75, 95% CI 0.53-0.96). Social contact at events demonstrated a positive impact (M=2.68) v. no contact (M = 2.42) on perceived attitude change; t(211)= 3.30, P=0.001. Contact quality predicted more positive attitude change (r=0.33, P<0.01) and greater confidence to challenge stigma (r=0.38, P<0.01).

Conclusions

The favourable short-term consequences of the social marketing campaign suggest that social contact can be used by anti-stigma programmes to reduce stigma.
The kinesin-like protein TOP promotes Aurora localisation and induces mitochondrial, chloroplast and nuclear division
Authors: Yoshida Yamato , Fujiwara Takayuki , Imoto Yuuta , Yoshida Masaki , Ohnuma Mio , Hirooka Shunsuke , Misumi Osami , Kuroiwa Haruko , Kato Shoichi , Matsunaga Sachihiro , Kuroiwa Tsuneyoshi
Published: April 2013

The cell cycle usually refers to the mitotic cycle, but the cell-division cycle in the plant kingdom consists of not only nuclear but also mitochondrial and chloroplast division cycle. However an integrated control system that initiates division of the three organelles has not been found. We first report that a novel C-terminal kinesin-like protein, three-organelle divisions inducing protein (TOP), controls nuclear, mitochondrial and chloroplast divisions in red alga Cyanidioschyzon merolae. A proteomics revealed that TOP was contained in the complex of mitochondrial-dividing (MD) and plastid-dividing (PD) machineries (MD/PD machinery complex) just prior to constriction. After TOP localized on the MD/PD machinery complex, mitochondrial and chloroplast divisions were performed and the components of the MD/PD machinery complexes were phosphorylated. Furthermore, TOP down-regulation impaired both mitochondrial and chloroplast divisions. MD/PD machinery complexes were formed normally at each division site but they were neither phosphorylated nor constricted in these cells. Immunofluorescence signals of Aurora kinase (AUR) were localized around the MD machinery before constriction whereas AUR was dispersed in cytosol by TOP down-regulation, suggesting that AUR is presumably required for the constriction. Taken together, TOP is likely to induce protein phosphorylation of MD/PD machinery components to accomplish mitochondrial and chloroplast divisions prior to nuclear division by transferring of AUR. Concurrently, the involvement of TOP in mitochondrial and chloroplast division, given the presence of TOP homologs throughout eukaryotes, may illuminate the original function of C-terminal kinesin-like proteins.
During post-natal human myogenesis, normal myotube size requires TRPC1 and TRPC4 mediated Ca2+ entry
Authors: Antigny Fabrice , Koenig Stéphane , Bernheim Laurent , Frieden Maud
Published: April 2013

Myogenesis involves expression of muscle-specific transcription factors such as myogenin and MEF2 (Myocyte Enhancer Factor 2), and is essentially regulated by fluctuations of cytosolic Ca2+ concentration. Recently we demonstrated that molecular players of Store-Operated Ca2+ Entry (SOCE), STIM (Stromal Interacting Molecule) and Orai were fundamental in the differentiation process of post-natal human myoblasts. Besides STIM and Orai proteins, the family of TRPC (Transient Receptor Potential Canonical) channels was shown to be part of SOCE in several cellular systems. In this study, we investigated the role of TRPC channels in the human myogenesis process. We demonstrate using siRNA strategy or dominant negative TRPC overexpression, that TRPC1 and TRPC4 participate in SOCE, are necessary for MEF2 expression, and allow the fusion process to generate myotubes of normal size. Conversely, the overexpression of STIM1 with TRPC4 or TRPC1 increased SOCE, accelerated myoblast fusion, and produced hypertrophic myotubes. Interestingly, in cells depleted of TRPC1 or TRPC4, the normalization of SOCE by increasing the extracellular calcium concentration or by overexpressing STIM1 or Orai1, was not sufficient to restore normal fusion process. A normal differentiation occurred only when TRPC channel was re-expressed. These findings indicate that Ca2+ entry mediated specifically by TRPC1 and TRPC4 allow the formation of normal-sized myotubes.
Reconstructing a B-cell clonal lineage. I. Statistical inference of unobserved ancestors
Authors: Kepler Thomas B
Published: April 2013

One of the key phenomena in the adaptive immune response to infection and immunization is affinity maturation, during which antibody genes are mutated and selected, typically resulting in a substantial increase in binding affinity to the eliciting antigen. Advances in technology on several fronts have made it possible to clone large numbers of heavy-chain light-chain pairs from individual B cells and thereby identify whole sets of clonally related antibodies. These collections could provide the information necessary to reconstruct their own history - the sequence of changes introduced into the lineage during the development of the clone - and to study affinity maturation in detail. But the success of such a program depends entirely on accurately inferring the founding ancestor and the other unobserved intermediates. Given a set of clonally related immunoglobulin V-region genes, the method described here allows one to compute the posterior distribution over their possible ancestors, thereby giving a thorough accounting of the uncertainty inherent in the reconstruction.

I demonstrate the application of this method on heavy-chain and light-chain clones, assess the reliability of the inference, and discuss the sources of uncertainty.
Gravitational Wave Detection by Interferometry (Ground and Space)
Authors: Rowan Sheila , Hough Jim
Published: April 2013

Significant progress has been made in recent years on the development of gravitational wave detectors. Sources such as coalescing compact binary systems, low-mass X-ray binaries, stellar collapses and pulsars are all possible candidates for detection. The most promising design of gravitational wave detector uses test masses a long distance apart and freely suspended as pendulums on Earth or in drag-free craft in space. The main theme of this review is a discussion of the mechanical and optical principles used in the various long baseline systems being built around the world — LIGO (USA), VIRGO (Italy/France), TAMA 300 (Japan) and GEO 600 (Germany/UK) — and in LISA, a proposed space-borne interferometer.
Gravitational-Wave Data Analysis. Formalism and Sample Applications: The Gaussian Case
Authors: Jaranowski Piotr , Królak Andrzej
Published: April 2013

The article reviews the statistical theory of signal detection in application to analysis of deterministic gravitational-wave signals in the noise of a detector. Statistical foundations for the theory of signal detection and parameter estimation are presented. Several tools needed for both theoretical evaluation of the optimal data analysis methods and for their practical implementation are introduced. They include optimal signal-to-noise ratio, Fisher matrix, false alarm and detection probabilities, ${\mathcal F}$-statistic, template placement, and fitting factor. These tools apply to the case of signals buried in a stationary and Gaussian noise. Algorithms to efficiently implement the optimal data analysis techniques are discussed. Formulas are given for a general gravitational-wave signal that includes as special cases most of the deterministic signals of interest.
The Confrontation between General Relativity and Experiment
Authors: Will Clifford M.
Published: April 2013

The status of experimental tests of general relativity and of theoretical frameworks for analyzing them is reviewed. Einstein’s equivalence principle (EEP) is well supported by experiments such as the Eötvös experiment, tests of special relativity, and the gravitational redshift experiment. Ongoing tests of EEP and of the inverse square law are searching for new interactions arising from unification or quantum gravity. Tests of general relativity at the post-Newtonian level have reached high precision, including the light deflection, the Shapiro time delay, the perihelion advance of Mercury, and the Nordtvedt effect in lunar motion. Gravitational wave damping has been detected in an amount that agrees with general relativity to better than half a percent using the Hulse-Taylor binary pulsar, and other binary pulsar systems have yielded other tests, especially of strong-field effects. When direct observation of gravitational radiation from astrophysical sources begins, new tests of general relativity will be possible.
Brane Effective Actions, Kappa-Symmetry and Applications
Authors: Simón Joan
Published: April 2013

This is a review on brane effective actions, their symmetries and some of their applications. Its first part covers the Green-Schwarz formulation of single M- and D-brane effective actions focusing on kinematical aspects: the identification of their degrees of freedom, the importance of world volume diffeomorphisms and kappa symmetry to achieve manifest spacetime covariance and supersymmetry, and the explicit construction of such actions in arbitrary on-shell supergravity backgrounds.

Its second part deals with applications. First, the use of kappa symmetry to determine supersymmetric world volume solitons. This includes their explicit construction in flat and curved backgrounds, their interpretation as Bogomol’nyi-Prasad-Sommerfield (BPS) states carrying (topological) charges in the supersymmetry algebra and the connection between supersymmetry and Hamiltonian BPS bounds. When available, I emphasise the use of these solitons as constituents in microscopic models of black holes. Second, the use of probe approximations to infer about the non-trivial dynamics of strongly-coupled gauge theories using the anti de Sitter/conformal field theory (AdS/CFT) correspondence. This includes expectation values of Wilson loop operators, spectrum information and the general use of D-brane probes to approximate the dynamics of systems with small number of degrees of freedom interacting with larger systems allowing a dual gravitational description.

Its final part briefly discusses effective actions for N D-branes and M2-branes. This includes both Super-Yang-Mills theories, their higher-order corrections and partial results in covariantising these couplings to curved backgrounds, and the more recent supersymmetric Chern-Simons matter theories describing M2-branes using field theory, brane constructions and 3-algebra considerations.
Binary Neutron Star Mergers
Authors: Faber Joshua A. , Rasio Frederic A.
Published: April 2013

We review the current status of studies of the coalescence of binary neutron star systems. We begin with a discussion of the formation channels of merging binaries and we discuss the most recent theoretical predictions for merger rates. Next, we turn to the quasi-equilibrium formalisms that are used to study binaries prior to the merger phase and to generate initial data for fully dynamical simulations. The quasi-equilibrium approximation has played a key role in developing our understanding of the physics of binary coalescence and, in particular, of the orbital instability processes that can drive binaries to merger at the end of their lifetimes. We then turn to the numerical techniques used in dynamical simulations, including relativistic formalisms, (magneto-)hydrodynamics, gravitational-wave extraction techniques, and nuclear microphysics treatments. This is followed by a summary of the simulations performed across the field to date, including the most recent results from both fully relativistic and microphysically detailed simulations. Finally, we discuss the likely directions for the field as we transition from the first to the second generation of gravitational-wave interferometers and while supercomputers reach the petascale frontier.
A History of Solar Activity over Millennia
Authors: Usoskin Ilya G.
Published: April 2013

Presented here is a review of present knowledge of the long-term behavior of solar activity on a multi-millennial timescale, as reconstructed using the indirect proxy method.

The concept of solar activity is discussed along with an overview of the special indices used to quantify different aspects of variable solar activity, with special emphasis upon sunspot number.

Over long timescales, quantitative information about past solar activity can only be obtained using a method based upon indirect proxy, such as the cosmogenic isotopes 14 C and 10Be in natural stratified archives (e.g., tree rings or ice cores). We give an historical overview of the development of the proxy-based method for past solar-activity reconstruction over millennia, as well as a description of the modern state. Special attention is paid to the verification and cross-calibration of reconstructions. It is argued that this method of cosmogenic isotopes makes a solid basis for studies of solar variability in the past on a long timescale (centuries to millennia) during the Holocene.

A separate section is devoted to reconstructions of strong solar-energetic-particle (SEP) events in the past, that suggest that the present-day average SEP flux is broadly consistent with estimates on longer timescales, and that the occurrence of extra-strong events is unlikely.

Finally, the main features of the long-term evolution of solar magnetic activity, including the statistics of grand minima and maxima occurrence, are summarized and their possible implications, especially for solar/stellar dynamo theory, are discussed.
Magnetic Fields in the Solar Convection Zone
Authors: Fan Yuhong
Published: April 2013

Active regions on the solar surface are generally thought to originate from a strong toroidal magnetic field generated by a deep seated solar dynamo mechanism operating at the base of the solar convection zone. Thus the magnetic fields need to traverse the entire convection zone before they reach the photosphere to form the observed solar active regions. Understanding this process of active region flux emergence is therefore a crucial component for the study of the solar cycle dynamo. This article reviews studies with regard to the formation and rise of active region scale magnetic flux tubes in the solar convection zone and their emergence into the solar atmosphere as active regions.
Evidence for Therapeutic Uses of Nebulized Lidocaine in the Treatment of Intractable Cough and Asthma
Authors: Slaton Rachel M , Thomas Rachel H , Mbathi Joseph Wallace
Published: April 2013

OBJECTIVE

To summarize the efficacy and safety data for use of nebulized lidocaine in intractable cough and asthma.

DATA SOURCES

A literature search was conducted using PubMed (through November 2012), International Pharmaceutical Abstracts (1970–December 2012), and Cochrane Library (up to 2012) with the search terms nebulization, nebulized or nebulised; administration, inhalation; cough; asthma; and lidocaine. Results were limited to human studies published in the English language. Referenced citations from relevant publications were also reviewed.

STUDY SELECTION AND DATA EXTRACTION

All articles identified from the data sources were reviewed for inclusion. Clinical trials and descriptive studies that discussed use of nebulized lidocaine for treatment of intractable cough and asthma were included in the review.

DATA SYNTHESIS

Seventeen studies were identified for review. Seven studies (6 descriptive studies and 1 clinical trial) evaluating the use of nebulized lidocaine in intractable cough reported efficacy in doses ranging from 10 mg to 400 mg. Five clinical trials in asthma showed conflicting results regarding improvement in pulmonary function and glucocorticoid-sparing effects. General improvements in pulmonary function as well as the initial bronchoconstriction induced by nebulized lidocaine in subjects with baseline bronchial hyperreactivity were investigated in 5 studies. Overall, the available evidence does not appear to preclude the use of lidocaine as a treatment option for intractable cough after failure of traditional cough suppressants. Data on its use for short-term glucocorticoid-sparing effects in asthma are conflicting. Study limitations, including design, small sample size, and inconsistencies in method and adjunctive therapies, should be considered. Nebulized lidocaine is well tolerated; however, reports of initial bronchoconstriction have occurred.

CONCLUSIONS

Although nebulized lidocaine is not first-line therapy in intractable cough and asthma, it may provide an alternative treatment option in patients who cannot tolerate or are unresponsive to other treatments. Appropriate monitoring precautions should be used to ensure patient safety.
Serotonergic and Adrenergic Drug Interactions Associated with Linezolid: A Critical Review and Practical Management Approach
Authors: Ramsey Tasha D , Lau Tim TY , Ensom Mary HH
Published: April 2013

OBJECTIVE

To describe the evidence for serotonergic and adrenergic drug interactions with linezolid and discuss clinical management strategies.

DATA SOURCES

A literature search of PubMed (1947–November 2012), MEDLINE (1946–November 2012), EMBASE (1974–November 2012), and International Pharmaceutical Abstracts (1970–November 2012) was conducted using the terms linezolid, drug interaction, serotonin syndrome, serotonin toxicity, sympathomimetic, serotonergic agents, and adrenergic agents. Citations of retrieved articles were also reviewed.

STUDY SELECTION AND DATA EXTRACTION

English-language articles describing coadministration of serotonergic or adrenergic agents with linezolid to humans were included. Studies published only in abstract form were excluded.

DATA SYNTHESIS

One prospective study, 6 retrospective studies, and 24 case reports were identified describing a serotonergic or adrenergic drug interaction. Incidence of serotonin syndrome in patients on linezolid and serotonergic agents ranged between 0.24% and 4%. Serotonergic agents determined to have probable (according to the Horn Drug Interaction Probability Scale) linezolid interactions in case reports included meperidine, citalopram, escitalopram, fluoxetine, paroxetine, sertraline, duloxetine, and venlafaxine. Serotonergic agent dose and duration of coadministration with linezolid did not appear to influence the occurrence of serotonin syndrome. Adrenergic medication coadministration was associated with a possible drug interaction as determined by the Horn Drug Interaction Probability Scale but did not appear to result in clinically significant drug interactions with linezolid.

CONCLUSIONS

Linezolid-associated serotonergic drug interactions occur more commonly than adrenergic interactions. Serotonergic interactions considered probable according to the Horn Drug Interaction Probability Scale do not appear to correlate with drug dosage; time of onset ranges from <1 to 20 days, and effect resolves in <1 to 5 days after discontinuation of offending agents. If coadministration of linezolid and a serotonergic agent cannot be avoided, clinicians should be aware of the symptoms and management of serotonergic toxicity; close monitoring is recommended and additional serotonergic agents should not be used. While adrenergic drug interactions with linezolid are less common in clinical practice, monitoring for signs of hypertension remains important.
Modulation of α Power and Functional Connectivity during Facial Affect Recognition
Authors: Popov Tzvetan , Miller Gregory A. , Rockstroh Brigitte , Weisz Nathan
Published: April 2013

Research has linked oscillatory activity in the α frequency range, particularly in sensorimotor cortex, to processing of social actions. Results further suggest involvement of sensorimotor α in the processing of facial expressions, including affect. The sensorimotor face area may be critical for perception of emotional face expression, but the role it plays is unclear. The present study sought to clarify how oscillatory brain activity contributes to or reflects processing of facial affect during changes in facial expression. Neuromagnetic oscillatory brain activity was monitored while 30 volunteers viewed videos of human faces that changed their expression from neutral to fearful, neutral, or happy expressions. Induced changes in α power during the different morphs, source analysis, and graph-theoretic metrics served to identify the role of α power modulation and cross-regional coupling by means of phase synchrony during facial affect recognition. Changes from neutral to emotional faces were associated with a 10–15 Hz power increase localized in bilateral sensorimotor areas, together with occipital power decrease, preceding reported emotional expression recognition. Graph-theoretic analysis revealed that, in the course of a trial, the balance between sensorimotor power increase and decrease was associated with decreased and increased transregional connectedness as measured by node degree. Results suggest that modulations in α power facilitate early registration, with sensorimotor cortex including the sensorimotor face area largely functionally decoupled and thereby protected from additional, disruptive input and that subsequent α power decrease together with increased connectedness of sensorimotor areas facilitates successful facial affect recognition.
Dissociation between Dorsal and Ventral Hippocampal Theta Oscillations during Decision-Making
Authors: Schmidt Brandy , Hinman James R. , Jacobson Tara K. , Szkudlarek Emily , Argraves Melissa , Escabí Monty A. , Markus Etan J.
Published: April 2013

Hippocampal theta oscillations are postulated to support mnemonic processes in humans and rodents. Theta oscillations facilitate encoding and spatial navigation, but to date, it has been difficult to dissociate the effects of volitional movement from the cognitive demands of a task. Therefore, we examined whether volitional movement or cognitive demands exerted a greater modulating factor over theta oscillations during decision-making. Given the anatomical, electrophysiological, and functional dissociations along the dorsal–ventral axis, theta oscillations were simultaneously recorded in the dorsal and ventral hippocampus in rats trained to switch between place and motor–response strategies.

Stark differences in theta characteristics were found between the dorsal and ventral hippocampus in frequency, power, and coherence. Theta power increased in the dorsal, but decreased in the ventral hippocampus, during the decision-making epoch. Interestingly, the relationship between running speed and theta power was uncoupled during the decision-making epoch, a phenomenon limited to the dorsal hippocampus. Theta frequency increased in both the dorsal and ventral hippocampus during the decision epoch, although this effect was greater in the dorsal hippocampus. Despite these differences, ventral hippocampal theta was responsive to the navigation task; theta frequency, power, and coherence were all affected by cognitive demands. Theta coherence increased within the dorsal hippocampus during the decision-making epoch on all three tasks. However, coherence selectively increased throughout the hippocampus (dorsal to ventral) on the task with new hippocampal learning. Interestingly, most results were consistent across tasks, regardless of hippocampal-dependent learning. These data indicate increased integration and cooperation throughout the hippocampus during information processing.
A Neuronal GPCR is Critical for the Induction of the Heat Shock Response in the NematodeC. elegans
Authors: Maman Moria , Carvalhal Marques Filipa , Volovik Yuli , Dubnikov Tatyana , Bejerano-Sagie Michal , Cohen Ehud
Published: April 2013

In the nematodeCaenorhabditis elegans, the heat shock response (HSR) is regulated at the organismal level by a network of thermosensory neurons that senses elevated temperatures and activates the HSR in remote tissues. Which neuronal receptors are required for this signaling mechanism and in which neurons they function are largely unanswered questions. Here we used worms that were engineered to exhibit RNA interference hypersensitivity in neurons to screen for neuronal receptors that are required for the activation of the HSR and identified a putative G-protein coupled receptor (GPCR) as a novel key component of this mechanism. This gene, which we termed GPCR thermal receptor 1 (gtr-1), is expressed in chemosensory neurons and has no role in heat sensing but is critically required for the induction of genes that encode heat shock proteins in non-neural tissues upon exposure to heat. Surprisingly, the knock-down ofgtr-1by RNA interference protected worms expressing the Alzheimer's-disease-linked aggregative peptide Aβ3–42from proteotoxicity but had no effect on lifespan. This study provides several novel insights: (1) it shows that chemosensory neurons play important roles in the nematode's HSR-regulating mechanism, (2) it shows that lifespan and heat stress resistance are separable, and (3) it strengthens the emerging notion that the ability to respond to heat comes at the expense of protein homeostasis (proteostasis).
Experience-Dependent Modulation of Feedback Integration during Singing: Role of the Right Anterior Insula
Authors: Kleber Boris , Zeitouni Anthony G. , Friberg Anders , Zatorre Robert J.
Published: April 2013

Somatosensation plays an important role in the motor control of vocal functions, yet its neural correlate and relation to vocal learning is not well understood. We used fMRI in 17 trained singers and 12 nonsingers to study the effects of vocal-fold anesthesia on the vocal-motor singing network as a function of singing expertise. Tasks required participants to sing musical target intervals under normal conditions and after anesthesia. At the behavioral level, anesthesia altered pitch accuracy in both groups, but singers were less affected than nonsingers, indicating an experience-dependent effect of the intervention. At the neural level, this difference was accompanied by distinct patterns of decreased activation in singers (cortical and subcortical sensory and motor areas) and nonsingers (subcortical motor areas only) respectively, suggesting that anesthesia affected the higher-level voluntary (explicit) motor and sensorimotor integration network more in experienced singers, and the lower-level (implicit) subcortical motor loops in nonsingers. The right anterior insular cortex (AIC) was identified as the principal area dissociating the effect of expertise as a function of anesthesia by three separate sources of evidence. First, it responded differently to anesthesia in singers (decreased activation) and nonsingers (increased activation). Second, functional connectivity between AIC and bilateral A1, M1, and S1 was reduced in singers but augmented in nonsingers. Third, increased BOLD activity in right AIC in singers was correlated with larger pitch deviation under anesthesia. We conclude that the right AIC and sensory-motor areas play a role in experience-dependent modulation of feedback integration for vocal motor control during singing.
HIV-1 Tat C Modulates Expression of miRNA-101 to Suppress VE-Cadherin in Human Brain Microvascular Endothelial Cells
Authors: Mishra Ritu , Singh Sunit Kumar
Published: April 2013

HIV-1 infection leads to the development of HIV-associated neurological disorders. The HIV-1 Tat protein has been reported to exert an adverse effect on blood–brain barrier integrity and permeability. Perturbation in permeability is mainly caused by disruptions in adherens junctions and tight junction proteins. We have identified HIV-1 Tat C-induced disruption of VE-cadherin mediated by miRNA-101 in human brain microvascular endothelial cells (BMVECs). HIV-1 Tat C increased the expression of miR-101, which led to downregulation of VE-cadherin. Overexpression of miR-101 resulted into the suppression of VE-cadherin. Inhibition of miR-101 by the miRNA inhibitor enhanced the expression of VE-cadherin. We have demonstrated that VE-cadherin is a direct target of miR-101 using a luciferase reporter assay, which showed that mutated VE-cadherin 3′UTR and miR-101 cotransfection did not change luciferase activity. By overexpression and knockdown of miR-101, we have demonstrated that the expression level of claudin-5 is governed by the expression of VE-cadherin. These findings demonstrate a novel mechanism for the regulation of barrier permeability by miR-101 via posttranscriptional regulation of VE-cadherin in human BMVECs exposed to the HIV-1 Tat C protein.
Sucrose Ingestion Induces Rapid AMPA Receptor Trafficking
Authors: Tukey David S. , Ferreira Jainne M. , Antoine Shannon O. , D'amour James A. , Ninan Ipe , Cabeza de Vaca Soledad , Incontro Salvatore , Wincott Charlotte , Horwitz Julian K. , Hartner Diana T. , Guarini Carlo B. , Khatri Latika , Goffer Yossef , Xu Duo , Titcombe Roseann F. , Khatri Megna , Marzan Dave S. , Mahajan Shahana S. , Wang Jing , Froemke Robert C. , Carr Kenneth D. , Aoki Chiye , Ziff Edward B.
Published: April 2013

The mechanisms by which natural rewards such as sugar affect synaptic transmission and behavior are largely unexplored. Here, we investigate regulation of nucleus accumbens synapses by sucrose intake. Previous studies have shown that AMPA receptor (AMPAR) trafficking is a major mechanism for regulating synaptic strength, and thatin vitro, trafficking of AMPARs containing the GluA1 subunit takes place by a two-step mechanism involving extrasynaptic and then synaptic receptor transport. We report that in rat, repeated daily ingestion of a 25% sucrose solution transiently elevated spontaneous locomotion and potentiated accumbens core synapses through incorporation of Ca2+-permeable AMPA receptors (CPARs), which are GluA1-containing, GluA2-lacking AMPARs. Electrophysiological, biochemical, and quantitative electron microscopy studies revealed that sucrose training (7 d) induced a stable (>24 h) intraspinous GluA1 population, and that in these rats a single sucrose stimulus rapidly (5 min) but transiently (<24 h) elevated GluA1 at extrasynaptic sites. CPARs and dopamine D1 receptors were requiredin vivofor elevated locomotion after sucrose ingestion. Significantly, a 7 d protocol of daily ingestion of a 3% solution of saccharin, a noncaloric sweetener, induced synaptic GluA1 similarly to 25% sucrose ingestion. These findings identify multistep GluA1 trafficking, previously describedin vitro, as a mechanism for acute regulation of synaptic transmissionin vivoby a natural orosensory reward. Trafficking is stimulated by a chemosensory pathway that is not dependent on the caloric value of sucrose.
The p38α MAPK Regulates Microglial Responsiveness to Diffuse Traumatic Brain Injury
Authors: Bachstetter Adam D. , Rowe Rachel K. , Kaneko Machi , Goulding Danielle , Lifshitz Jonathan , Van Eldik Linda J.
Published: April 2013

Neuropathology after traumatic brain injury (TBI) is the result of both the immediate impact injury and secondary injury mechanisms. Unresolved post-traumatic glial activation is a secondary injury mechanism that contributes to a chronic state of neuroinflammation in both animal models of TBI and human head injury patients. We recently demonstrated, usingin vitromodels, that p38α MAPK signaling in microglia is a key event in promoting cytokine production in response to diverse disease-relevant stressors and subsequent inflammatory neuronal dysfunction. From these findings, we hypothesized that the p38α signaling pathway in microglia could be contributing to the secondary neuropathologic sequelae after a diffuse TBI. Mice where microglia were p38α-deficient (p38α KO) were protected against TBI-induced motor deficits and synaptic protein loss. In wild-type (WT) mice, diffuse TBI produced microglia morphological activation that lasted for at least 7 d; however, p38α KO mice failed to activate this response. Unexpectedly, we found that the peak of the early, acute phase cytokine and chemokine levels was increased in injured p38α KO mice compared with injured WT mice. The increased cytokine levels in the p38α KO mice could not be accounted for by more infiltration of macrophages or neutrophils, or increased astrogliosis. By 7 d after injury, the cytokine and chemokine levels remained elevated in injured WT mice but not in p38α KO mice. Together, these data suggest that p38α balances the inflammatory response by acutely attenuating the early proinflammatory cytokine surge while perpetuating the chronic microglia activation after TBI.