bluuebunny/crossref_metadata_2025 huggingface dataset:
Structure of central and southern Mexico from velocity and attenuation tomography
Authors: Chen Ting , Clayton Robert W.
Published: July 2012

The 3DVp,Vp/Vs, P‐ and S‐wave attenuation structure of the Cocos subduction zone in Mexico is imaged using earthquakes recorded by two temporary seismic arrays and local stations. Direct P wave arrivals on vertical components and direct S wave arrivals on transverse components from local earthquakes are used for velocity imaging. Relative delay times for P and PKP phases from teleseismic events are also used to obtain a deeper velocity structure beneath the southern seismic array. Using a spectral‐decay method, we calculate a path attenuation operatort* for each P and S waveform from local events, and then invert for 3D spatial variations in attenuation (Qp−1andQs−1). Inversion results reveal a low‐attenuation and high‐velocity Cocos slab. The slab dip angle increases from almost flat in central Mexico near Mexico City to about 30° in southern Mexico near the Isthmus of Tehuantepec. High attenuation and low velocity in the crust beneath the Trans‐Mexico Volcanic Belt correlate with low resistivity, and are probably related to dehydration of the slab and melting processes. The most pronounced high‐attenuation, low‐Vpand high‐Vp/Vsanomaly is found in the crust beneath the Veracruz Basin. A high‐velocity structure dipping into the mantle from the side of Gulf of Mexico coincides with a discontinuity from a receiver functions study, and provides an evidence for the collision between the Yucatán Block and Mexico in the Miocene.
Trends of upper‐layer circulation in the South China Sea during 1959–2008
Authors: Yang Haiyuan , Wu Lixin
Published: July 2012

In this paper, the trend of upper‐layer circulation in the South China Sea (SCS) is studied based on the Simple Ocean Data Assimilation product for 1959–2008. It is found that the basin‐averaged SST in winter displays a warming rate close to the global mean value while it does not have significant trend in summer. The upper‐layer circulation in the SCS has been weakened in winter by 10% over this period, while in summer it tends to be more energetic. Further analyses suggest that the weakening of the winter SCS ocean circulation in winter is associated with weakening of the East Asian monsoon over recent decades. Moreover, an eastward retreat of the anti‐cyclonic “Kuroshio loop” from the SCS is found, which may be due to an intensification of the Kuroshio transport in the past 50 years.
Chemical composition of tropospheric air masses encountered during high altitude flights (>11.5 km) during the 2009 fall Operation Ice Bridge field campaign
Authors: Yang Mei Ying Melissa , Vay Stephanie A. , Stohl Andreas , Choi Yonghoon , Diskin Glenn S. , Sachse Glen W. , Blake Donald R.
Published: July 2012

As part of the 2009 Operation Ice Bridge campaign, the NASA DC‐8 aircraft was used to fill the data‐time gap in laser observation of the changes in ice sheets, glaciers and sea ice between ICESat‐I (Ice, Cloud, and land Elevation Satellite) and ICESat‐II. Complementing the cryospheric instrument payload were four in situ atmospheric sampling instruments integrated onboard to measure trace gas concentrations of CO2, CO, N2O, CH4, water vapor and various VOCs (Volatile Organic Compounds). This paper examines two plumes encountered at high altitude (12 km) during the campaign; one during a southbound transit flight (13°S) and the other at 86°S over Antarctica. The data presented are especially significant as the Southern Hemisphere is heavily under‐sampled during the austral spring, with few if any high‐resolution airborne observations of atmospheric gases made over Antarctica. Strong enhancements of CO, CH4, N2O, CHCl3, OCS, C2H6, C2H2 and C3H8 were observed in the two intercepted air masses that exhibited variations in VOC composition suggesting different sources. The transport model FLEXPART showed that the 13°S plume contained predominately biomass burning emissions originating from Southeast Asia and South Africa, while both anthropogenic and biomass burning emissions were observed at 86°S with South America and South Africa as indicated source regions. The data presented here show evidence that boundary layer pollution is transported from lower latitudes toward the upper troposphere above the South Pole, which may not have been observed in the past.
Dedifferentiated follicular granulosa cells derived from pig ovary can transdifferentiate into osteoblasts
Authors: Oki Yoshinao , Ono Hiromasa , Motohashi Takeharu , Sugiura Nobuki , Nobusue Hiroyuki , Kano Koichiro
Published: July 2012

Transdifferentiation is the conversion of cells from one differentiated cell type into another. How functionally differentiated cells already committed to a specific cell lineage can transdifferentiate into other cell types is a key question in cell biology and regenerative medicine. In the present study we show that porcine ovarian follicular GCs (granulosa cells) can transdifferentiate into osteoblasts in vitro and in vivo. Pure GCs isolated and cultured in Dulbecco's modified Eagle's medium supplemented with 20% FBS (fetal bovine serum) proliferated and dedifferentiated into fibroblast-like cells. We referred to these cells as DFOG (dedifferentiated follicular granulosa) cells. Microarray analysis showed that DFOG cells lost expression of GC-specific marker genes, but gained the expression of osteogenic marker genes during dedifferentiation. After osteogenic induction, DFOG cells underwent terminal osteoblast differentiation and matrix mineralization in vitro. Furthermore, when DFOG cells were transplanted subcutaneously into SCID mice, these cells formed ectopic osteoid tissue. These results indicate that DFOG cells derived from GCs can differentiate into osteoblasts in vitro and in vivo. We suggest that GCs provide a useful model for studying the mechanisms of transdifferentiation into other cell lineages in functionally differentiated cells.
Digoxin and ouabain induce the efflux of cholesterol via liver X receptor signalling and the synthesis of ATP in cardiomyocytes
Authors: Campia Ivana , Sala Valentina , Kopecka Joanna , Leo Christian , Mitro Nico , Costamagna Costanzo , Caruso Donatella , Pescarmona Gianpiero , Crepaldi Tiziana , Ghigo Dario , Bosia Amalia , Riganti Chiara
Published: July 2012

Cardioactive glycosides exert positive inotropic effects on cardiomyocytes through the inhibition of Na+/K+-ATPase. We showed previously that in human hepatoma cells, digoxin and ouabain increase the rate of the mevalonate cascade and therefore have Na+/K+-ATPase-independent effects. In the present study we found that they increase the expression and activity of 3-hydroxy-3 methylglutaryl-CoA reductase and the synthesis of cholesterol in cardiomyocytes, their main target cells. Surprisingly this did not promote intracellular cholesterol accumulation. The glycosides activated the liver X receptor transcription factor and increased the expression of ABCA1 (ATP-binding cassette protein A1) transporter, which mediates the efflux of cholesterol and its delivery to apolipoprotein A-I. By increasing the synthesis of ubiquinone, another derivative of the mevalonate cascade, digoxin and ouabain simultaneously enhanced the rate of electron transport in the mitochondrial respiratory chain and the synthesis of ATP. Mice treated with digoxin showed lower cholesterol and higher ubiquinone content in their hearts, and a small increase in their serum HDL (high-density lipoprotein) cholesterol. The results of the present study suggest that cardioactive glycosides may have a role in the reverse transport of cholesterol and in the energy metabolism of cardiomyocytes.
Molecular structure of human GM-CSF in complex with a disease-associated anti-human GM-CSF autoantibody and its potential biological implications
Authors: Blech Michaela , Seeliger Daniel , Kistler Barbara , Bauer Margit M. T. , Hafner Mathias , Hörer Stefan , Zeeb Markus , Nar Herbert , Park John E.
Published: July 2012

Polyclonal autoantibodies against human GM-CSF (granulocyte/macrophage colony-stimulating factor) are a hallmark of PAP (pulmonary alveolar proteinosis) and several other reported autoimmune diseases. MB007 is a high-affinity anti-(human GM-CSF) autoantibody isolated from a patient suffering from PAP which shows only modest neutralization of GM-CSF bioactivity. We describe the first crystal structure of a cytokine-directed human IgG1λ autoantibody-binding fragment (Fab) at 1.9 Å (1 Å=0.1 nm) resolution. Its CDR3-H substantially differs from all VH7 germline IgG1 structures reported previously. We derive a reliable model of the antigen–autoantibody complex by using NMR chemical shift perturbation data in combination with computational methods. Superposition of the modelled complex structure with the human GM-CSF–GM-CSF ternary receptor complex reveals only little overlap between receptor and Fab when bound to GM-CSF. Our model provides a structural basis for understanding the mode of action of the MB007 autoantibody.
Maxillofacial Trauma in Central Karnataka, India: An Outcome of 95 Cases in a Regional Trauma Care Centre
Authors: Kamath Rajay A. D. , Bharani Shiva , Hammannavar Reshma , Ingle Sumit P. , Shah Ankit G.
Published: July 2012

Materials and Methods

A 6-year retrospective analysis of 111 patients treated for maxillofacial fractures in Davangere, Karnataka from January 2004 to December 2009 was performed. Variables like age, gender, occupation, type of fracture and mechanism of injury, concomitant injury, mode of treatment, and complications were recorded and assessed.

Results

Men between 21 and 30 years were mostly affected (male-to-female ratio = 10:1; age range = 17.60 years; mean 31.7±9.8 [standard deviation]). Most fractures were caused by road traffic accidents (RTAs; 74.7%), followed by interpersonal violence (IPV; 15.8%), falls (4.2%), industrial hazards and animal attacks (2.1% each), and self-inflicted injury (1.1%). Forty-two cases were isolated zygomaticomaxillary complex (ZMC) fractures. The total number of facial fractures documented was 316, of which 222 were purely related to the ZMC; however, 11 were confined only to the midface. Fifty-three cases had concomitant lower jaw fractures, totaling 83. Ophthalmic injuries occurred in 30.52% of cases. Ninety-two cases were treated with open reduction and internal fixation (ORIF), and three cases were managed conservatively. The complication rate observed was 25.26%.

Conclusion

RTA continues to be the chief etiological factor in maxillofacial injury with males being affected predominantly. IPV and falls next contribute significantly to the incidence of such injuries. Concomitant injuries, however, require prompt recognition and appropriate management. ORIF still remains the mainstay of treatment; however, fixation devices are constantly being improved upon in an attempt to reduce immobilization time thereby facilitating early return to function with minimal morbidity. Nevertheless, future advances in maxillofacial trauma diagnosis and management are likely to reduce associated morbidity.
Molecular mechanism for the interaction between gibberellin and brassinosteroid signaling pathways in
Arabidopsis
Authors: Gallego-Bartolomé Javier , Minguet Eugenio G. , Grau-Enguix Federico , Abbas Mohamad , Locascio Antonella , Thomas Stephen G. , Alabadí David , Blázquez Miguel A.
Published: July 2012

Plant development is modulated by the convergence of multiple environmental and endogenous signals, and the mechanisms that allow the integration of different signaling pathways is currently being unveiled. A paradigmatic case is the concurrence of brassinosteroid (BR) and gibberellin (GA) signaling in the control of cell expansion during photomorphogenesis, which is supported by physiological observations in several plants but for which no molecular mechanism has been proposed. In this work, we show that the integration of these two signaling pathways occurs through the physical interaction between the DELLA protein GAI, which is a major negative regulator of the GA pathway, and BRASSINAZOLE RESISTANT1 (BZR1), a transcription factor that broadly regulates gene expression in response to BRs. We provide biochemical evidence, both in vitro and in vivo, indicating that GAI inactivates the transcriptional regulatory activity of BZR1 upon their interaction by inhibiting the ability of BZR1 to bind to target promoters. The physiological relevance of this interaction was confirmed by the observation that the dominant
gai-1
allele interferes with BR-regulated gene expression, whereas the
bzr1-1D
allele displays enhanced resistance to DELLA accumulation during hypocotyl elongation. Because DELLA proteins mediate the response to multiple environmental signals, our results provide an initial molecular framework for the integration with BRs of additional pathways that control plant development.
Liquid-infused structured surfaces with exceptional anti-biofouling performance
Authors: Epstein Alexander K. , Wong Tak-Sing , Belisle Rebecca A. , Boggs Emily Marie , Aizenberg Joanna
Published: July 2012

Bacteria primarily exist in robust, surface-associated communities known as biofilms, ubiquitous in both natural and anthropogenic environments. Mature biofilms resist a wide range of antimicrobial treatments and pose persistent pathogenic threats. Treatment of adherent biofilm is difficult, costly, and, in medical systems such as catheters or implants, frequently impossible. At the same time, strategies for biofilm prevention based on surface chemistry treatments or surface microstructure have been found to only transiently affect initial attachment. Here we report that Slippery Liquid-Infused Porous Surfaces (SLIPS) prevent 99.6% ofPseudomonas aeruginosabiofilm attachment over a 7-d period, as well asStaphylococcus aureus(97.2%) andEscherichia coli(96%), under both static and physiologically realistic flow conditions. In contrast, both polytetrafluoroethylene and a range of nanostructured superhydrophobic surfaces accumulate biofilm within hours. SLIPS show approximately 35 times the reduction of attached biofilm versus best case scenario, state-of-the-art PEGylated surface, and over a far longer timeframe. We screen for and exclude as a factor cytotoxicity of the SLIPS liquid, a fluorinated oil immobilized on a structured substrate. The inability of biofilm to firmly attach to the surface and its effective removal under mild flow conditions (about 1 cm/s) are a result of the unique, nonadhesive, “slippery” character of the smooth liquid interface, which does not degrade over the experimental timeframe. We show that SLIPS-based antibiofilm surfaces are stable in submerged, extreme pH, salinity, and UV environments. They are low-cost, passive, simple to manufacture, and can be formed on arbitrary surfaces. We anticipate that our findings will enable a broad range of antibiofilm solutions in the clinical, industrial, and consumer spaces.
A molecular method for the delivery of small molecules and proteins across the cell wall of algae using molecular transporters
Authors: Hyman Joel M. , Geihe Erika I. , Trantow Brian M. , Parvin Bahram , Wender Paul A.
Published: July 2012

Interest in algae has significantly accelerated with the increasing recognition of their potentially unique role in medical, materials, energy, bioremediation, and synthetic biological research. However, the introduction of tools to study, control, or expand the inner-workings of algae has lagged behind. Here we describe a general molecular method based on guanidinium-rich molecular transporters (GR-MoTrs) for bringing small and large cargos into algal cells. Significantly, this method is shown to work in wild-type algae that have an intact cell wall. Developed using
Chlamydomonas reinhardtii
, this method is also successful with less studied algae including
Neochloris oleoabundans
and
Scenedesmus dimorphus
thus providing a new and versatile tool for algal research.
Molecular basis for the specification of floral organs by APETALA3 and PISTILLATA
Authors: Wuest Samuel E. , O’Maoileidigh Diarmuid S. , Rae Liina , Kwasniewska Kamila , Raganelli Andrea , Hanczaryk Katarzyna , Lohan Amanda J. , Loftus Brendan , Graciet Emmanuelle , Wellmer Frank
Published: July 2012

How different organs are formed from small sets of undifferentiated precursor cells is a key question in developmental biology. To understand the molecular mechanisms underlying organ specification in plants, we studied the function of the homeotic selector genes
APETALA3
(
AP3
) and
PISTILLATA
(
PI
), which control the formation of petals and stamens during
Arabidopsis
flower development. To this end, we characterized the activities of the transcription factors that
AP3
and
PI
encode throughout flower development by using perturbation assays as well as transcript profiling and genomewide localization studies, in combination with a floral induction system that allows a stage-specific analysis of flower development by genomic technologies. We discovered considerable spatial and temporal differences in the requirement for AP3/PI activity during flower formation and show that they control different sets of genes at distinct phases of flower development. The genomewide identification of target genes revealed that AP3/PI act as bifunctional transcription factors: they activate genes involved in the control of numerous developmental processes required for organogenesis and repress key regulators of carpel formation. Our results imply considerable changes in the composition and topology of the gene network controlled by AP3/PI during the course of flower development. We discuss our results in light of a model for the mechanism underlying sex-determination in seed plants, in which AP3/PI orthologues might act as a switch between the activation of male and the repression of female development.
c-kit
+
precursors support postinfarction myogenesis in the neonatal, but not adult, heart
Authors: Jesty Sophy A. , Steffey Michele A. , Lee Frank K. , Breitbach Martin , Hesse Michael , Reining Shaun , Lee Jane C. , Doran Robert M. , Nikitin Alexander Yu. , Fleischmann Bernd K. , Kotlikoff Michael I.
Published: July 2012

We examined the myogenic response to infarction in neonatal and adult mice to determine the role of c-kit
+
cardiovascular precursor cells (CPC) that are known to be present in early heart development. Infarction of postnatal day 1–3 c-kit
BAC
-EGFP mouse hearts induced the localized expansion of (c-kit)EGFP
+
cells within the infarct, expression of the c-kit and Nkx2.5 mRNA, myogenesis, and partial regeneration of the infarction, with (c-kit)EGFP
+
cells adopting myogenic and vascular fates. Conversely, infarction of adult mice resulted in a modest induction of (c-kit)EGFP
+
cells within the infarct, which did not express Nkx2.5 or undergo myogenic differentiation, but adopted a vascular fate within the infarction, indicating a lack of authentic CPC. Explantation of infarcted neonatal and adult heart tissue to
scid
mice, and adoptive transfer of labeled bone marrow, confirmed the cardiac source of myogenic (neonate) and angiogenic (neonate and adult) cells. FACS-purified (c-kit)EGFP
+
/(αMHC)mCherry
−
(noncardiac) cells from microdissected infarcts within 6 h of infarction underwent cardiac differentiation, forming spontaneously beating myocytes in vitro; cre/LoxP fate mapping identified a noncardiac population of (c-kit)EGFP
+
myocytes within infarctions, indicating that the induction of undifferentiated precursors contributes to localized myogenesis. Thus, adult postinfarct myogenic failure is likely not due to a context-dependent restriction of precursor differentiation, and c-kit induction following injury of the adult heart does not define precursor status.
Molecular basis of bacterial protein Hen1 activating the ligase activity of bacterial protein Pnkp for RNA repair
Authors: Wang Pei , Chan Chio Mui , Christensen David , Zhang Can , Selvadurai Kiruthika , Huang Raven H.
Published: July 2012

Ribotoxins cleave essential RNAs for cell killing in vivo, and the bacterial polynucleotide kinase-phosphatase (Pnkp)/hua enhancer 1 (Hen1) complex has been shown to repair ribotoxin-cleaved RNAs in vitro. Bacterial Pnkp/Hen1 is distinguished from other RNA repair systems by performing 3′-terminal 2′-O-methylation during RNA repair, which prevents the repaired RNA from repeated cleavage at the same site. To ensure the opportunity of 2′-O-methylation by bacterial Hen1 during RNA repair and, therefore, maintain the quality of the repaired RNA, Pnkp/Hen1 has evolved to require the participation of Hen1 in RNA ligation, because Pnkp alone is unable to carry out the reaction despite possessing all signature motifs of an RNA ligase. However, the precise role of Hen1 in RNA ligation is unknown. Here, we present the crystal structure of an active RNA ligase consisting of the C-terminal half of Pnkp (Pnkp-C) and the N-terminal half of Hen1 (Hen1-N) from
Clostridium thermocellum
. The structure reveals that the N-terminal domain of
Clostridium thermocellum
(
Cth
) Hen1, shaped like a left hand, grabs the flexible insertion module of
Cth
Pnkp and locks its conformation via further interaction with the C-terminal addition module of
Cth
Pnkp. Formation of the
Cth
Pnkp-C/Hen1-N heterodimer creates a ligation pocket with a width for two strands of RNA, depth for two nucleotides, and the adenosine monophosphate (AMP)-binding pocket at the bottom. The structure, combined with functional analyses, provides insight into the mechanism of how Hen1 activates the RNA ligase activity of Pnkp for RNA repair.
Dynamics of inherently bounded histone modification domains
Authors: Hodges Courtney , Crabtree Gerald R.
Published: July 2012

A central goal of chromatin biology is to reveal how posttranslational histone marks modulate gene expression; however, relatively little is known about the spatial or temporal dynamics of these marks. We previously showed that a dynamic model of histone mark nucleation, propagation, and turnover fits the mean enrichment profiles from 99% of noncentromeric histone H3 lysine 9 trimethylation (H3K9me3) domains in mouse embryonic stem cells without the need for boundary or insulator elements. Here we report the full details of this “inherently bounded” model of histone modification dynamics and describe several dynamic features of the model using H3K9me3 as a paradigm. By analyzing the kinetic and structural constraints that drive formation of inherently bounded domains, we find that such domains are optimized when the rates of marking and turnover are comparable. Additionally, we find that to establish such domains, propagation of the histone marks must occur primarily through local contacts.
Mammalian ribonucleotide reductase subunit p53R2 is required for mitochondrial DNA replication and DNA repair in quiescent cells
Authors: Pontarin Giovanna , Ferraro Paola , Bee Leonardo , Reichard Peter , Bianchi Vera
Published: July 2012

In postmitotic mammalian cells, protein p53R2 substitutes for protein R2 as a subunit of ribonucleotide reductase. In human patients with mutations in
RRM2B
, the gene for p53R2, mitochondrial (mt) DNA synthesis is defective, and skeletal muscle presents severe mtDNA depletion. Skin fibroblasts isolated from a patient with a lethal homozygous missense mutation of p53R2 grow normally in culture with an unchanged complement of mtDNA. During active growth, the four dNTP pools do not differ in size from normal controls, whereas during quiescence, the dCTP and dGTP pools decrease to 50% of the control. We investigate the ability of these mutated fibroblasts to synthesize mtDNA and repair DNA after exposure to UV irradiation. Ethidium bromide depleted both mutant and normal cells of mtDNA. On withdrawal of the drug, mtDNA recovered equally well in cycling mutant and control cells, whereas during quiescence, the mutant fibroblasts remained deficient. Addition of deoxynucleosides to the medium increased intracellular dNTP pools and normalized mtDNA synthesis. Quiescent mutant fibroblasts were also deficient in the repair of UV-induced DNA damage, as indicated by delayed recovery of dsDNA analyzed by fluorometric analysis of DNA unwinding and the more extensive and prolonged phosphorylation of histone H2AX after irradiation. Supplementation by deoxynucleosides improved DNA repair. Our results show that in nontransformed cells only during quiescence, protein p53R2 is required for maintenance of mtDNA and for optimal DNA repair after UV damage.
Outgrowing meiosis
Authors: Leslie Mitch
Published: July 2012

Study finds that a fertilized egg doesn't immediately start dividing mitotically.
Deep architectures for protein contact map prediction
Authors: Di Lena Pietro , Nagata Ken , Baldi Pierre
Published: July 2012

Motivation: Residue–residue contact prediction is important for protein structure prediction and other applications. However, the accuracy of current contact predictors often barely exceeds 20% on long-range contacts, falling short of the level required for ab initio structure prediction.

Results: Here, we develop a novel machine learning approach for contact map prediction using three steps of increasing resolution. First, we use 2D recursive neural networks to predict coarse contacts and orientations between secondary structure elements. Second, we use an energy-based method to align secondary structure elements and predict contact probabilities between residues in contacting alpha-helices or strands. Third, we use a deep neural network architecture to organize and progressively refine the prediction of contacts, integrating information over both space and time. We train the architecture on a large set of non-redundant proteins and test it on a large set of non-homologous domains, as well as on the set of protein domains used for contact prediction in the two most recent CASP8 and CASP9 experiments. For long-range contacts, the accuracy of the new CMAPpro predictor is close to 30%, a significant increase over existing approaches.

Availability: CMAPpro is available as part of the SCRATCH suite at http://scratch.proteomics.ics.uci.edu/.

Contact:  pfbaldi@uci.edu

Supplementary information:  Supplementary data are available at Bioinformatics online.
An integrated approach to reduce the impact of minor allele frequency and linkage disequilibrium on variable importance measures for genome-wide data
Authors: Walters Raymond , Laurin Charles , Lubke Gitta H.
Published: July 2012

Motivation: There is growing momentum to develop statistical learning (SL) methods as an alternative to conventional genome-wide association studies (GWAS). Methods such as random forests (RF) and gradient boosting machine (GBM) result in variable importance measures that indicate how well each single-nucleotide polymorphism (SNP) predicts the phenotype. For RF, it has been shown that variable importance measures are systematically affected by minor allele frequency (MAF) and linkage disequilibrium (LD). To establish RF and GBM as viable alternatives for analyzing genome-wide data, it is necessary to address this potential bias and show that SL methods do not significantly under-perform conventional GWAS methods.

Results: Both LD and MAF have a significant impact on the variable importance measures commonly used in RF and GBM. Dividing SNPs into overlapping subsets with approximate linkage equilibrium and applying SL methods to each subset successfully reduces the impact of LD. A welcome side effect of this approach is a dramatic reduction in parallel computing time, increasing the feasibility of applying SL methods to large datasets. The created subsets also facilitate a potential correction for the effect of MAF using pseudocovariates. Simulations using simulated SNPs embedded in empirical data—assessing varying effect sizes, minor allele frequencies and LD patterns—suggest that the sensitivity to detect effects is often improved by subsetting and does not significantly under-perform the Armitage trend test, even under ideal conditions for the trend test.

Availability: Code for the LD subsetting algorithm and pseudocovariate correction is available at http://www.nd.edu/∼glubke/code.html.

Contact:  glubke@nd.edu

Supplementary information: Supplementary data are available at Bioinformatics online.
Autonomic markers and cardiovascular and arrhythmic events in heart failure patients: still a place in prognostication? Data from the GISSI‐HF trial
Authors: La Rovere Maria Teresa , Pinna Gian Domenico , Maestri Roberto , Barlera Simona , Bernardinangeli Marino , Veniani Marco , Nicolosi Gian Luigi , Marchioli Roberto , Tavazzi Luigi ,   for the GISSI‐HF Investigators
Published: July 2012

Aims

To investigate the prognostic value of autonomic variables in patients with symptomatic chronic heart failure (HF) treated according to current recommendations.

Methods and results

We analysed 24 h time‐domain [standard deviation of all normal‐to‐normal RR intervals (SDNN)], frequency‐domain [very low frequency and low frequency power (VFLP and LFP)], and non‐linear [detrended fluctuation analysis (DFA)] heart rate variability, deceleration capacity (DC), and heart rate turbulence (HRT) in 388 sinus rhythm HF patients enrolled in the GISSI‐HF Holter substudy [82% males, age 65 ±10 years, New York Heart Association (NYHA) functional class III–IV 20%, left ventricular ejection fraction (LVEF) 33 ±8%]. Cardiovascular (CV) mortality and combined sudden death + implantable cardioverter defibrillator (ICD) discharge were assessed as a function of continuous variables in the entire population and in patients with LVEF >30% in univariate and multivariable Cox proportional hazards models. After a median of 47 months, 57 patients died of CV causes and 47 experienced the arrhythmic endpoint. For CV mortality, VLFP, LFP, and turbulence slope (TS) improved predictive discrimination (c‐index) and risk classification [integrated discrimination improvement (IDI)] when added to clinical variables [age ≥70 years, LVEF, non‐sustained ventricular tachycardia (NSVT), serum creatinine], while for arrhythmic mortality although the c‐index increased in all three autonomic markers, the results of the IDI were statistically significant only for TS when added to NSVT, serum creatinine, and ischaemic aetiology. In 194 patients with LVEF >30% (20 arrhythmic events), the hazard ratio of an impaired TS (<2.5 msper RR interval) was 3.81 (95% confidence interval 1.35–10.7,P = 0.012) after adjustment for serum creatinine.

Conclusions

Autonomic indexes still have independent predictive value on long‐term outcome in HF patients. HRT may help in identifying patients with LVEF >30% at increased arrhythmic risk.

Trial registration NCT00336336
Depressive-like States Heighten the Aversion to Painful Stimuli in a Rat Model of Comorbid Chronic Pain and Depression
Authors: Bravo Lidia , Mico Juan Antonio , Rey-Brea Raquel , Pérez-Nievas Beatriz , Leza Juan Carlos , Berrocoso Esther
Published: July 2012

Background

Chronic pain and depression are two complex states with sensory/somatic and emotional components, and they may mutually exacerbate one another in conditions of comorbidity, leading to a poorer prognosis.

Methods

The authors have evaluated the sensory and emotional components in a rat model combining chronic constriction injury (CCI, a model of chronic neuropathic pain) with unpredictable chronic mild stress (CMS, an experimental model of depression). In addition, the phosphorylation/activation of the extracellular signal-regulated kinases 1 and 2 and neuronal density was also evaluated in the anterior cingulate cortex. Four groups were tested: sham-control, sham-CMS, CCI-control, and CCI-CMS.

Results

CMS selectively heightens aversion to painful experiences in animals subjected to CCI, as measured in the place escape/avoidance test at 20, 25, and 30 min (CCI-CMS (mean±SEM): 75.68±3.32, 66.75±4.70, 77.54±3.60 vs. CCI-control: 44.66±6.07, 43.17±6.92, 52.83±5.92, respectively), in conjunction with an increase in the accumulation of phosphorylation/activation of the extracellular signal-regulated kinases (CCI-CMS: 4.17±0.52 vs. sham-control: 0.96±0.05) and a decrease in neuronal density in the anterior cingulate cortex. In contrast, chronic pain did not exacerbate the characteristic profile of depression (anhedonia and behavioral despair) in rats subjected to CMS. Furthermore, depression enhances the perception of some specific modalities of sensorial pain such as cold allodynia but has no influence on mechanical threshold.

Conclusions

These findings support the theory that depression leads to emotional dysfunction in the interpretation of pain in patients suffering chronic pain. In addition, combined animal models of pain-depression may provide a valuable tool to study the comorbidity of pain and depression.
Antimetastatic Potential of Amide-linked Local Anesthetics
Authors: Piegeler Tobias , Votta-Velis E. Gina , Liu Guoquan , Place Aaron T. , Schwartz David E. , Beck-Schimmer Beatrice , Minshall Richard D. , Borgeat Alain
Published: July 2012

Background

Retrospective analysis of patients undergoing cancer surgery suggests the use of regional anesthesia may reduce cancer recurrence and improve survival. Amide-linked local anesthetics have antiinflammatory properties, although the mechanism of action in this regard is unclear. As inflammatory processes involving Src tyrosine protein kinase and intercellular adhesion molecule-1 are important in tumor growth and metastasis, we hypothesized that amide-linked local anesthetics may inhibit inflammatory Src-signaling involved in migration of adenocarcinoma cells.

Methods

NCI-H838 lung cancer cells were incubated with tumor necrosis factor-α in absence/presence of ropivacaine, lidocaine, or chloroprocaine (1 nM-100 μM). Cell migration and total cell lysate Src-activation and intercellular adhesion molecule-1 phosphorylation were assessed. The role of voltage-gated sodium-channels in the mechanism of local anesthetic effects was also evaluated.

Results

Ropivacaine treatment (100 μM) of H838 cells for 20 min decreased basal Src activity by 62% (P=0.003), and both ropivacaine and lidocaine coadministered with tumor necrosis factor-α statistically significantly decreased Src-activation and intercellular adhesion molecule-1 phosphorylation, whereas chloroprocaine had no such effect. Migration of these cells at 4 h was inhibited by 26% (P=0.005) in presence of 1 μM ropivacaine and 21% by 1 μM lidocaine (P=0.004). These effects of ropivacaine and lidocaine were independent of voltage-gated sodium-channel inhibition.

Conclusions

This study indicates that amide-, but not ester-linked, local anesthetics may provide beneficial antimetastatic effects. The observed inhibition of NCI-H838 cell migration by lidocaine and ropivacaine was associated with the inhibition of tumor necrosis factor-α-induced Src-activation and intercellular adhesion molecule-1 phosphorylation, providing the first evidence of a molecular mechanism that appears to be independent of their known role as sodium-channel blockers.
Effects of Muscle Relaxants on Mask Ventilation in Anesthetized Persons with Normal Upper Airway Anatomy
Authors: Ikeda Aya , Isono Shiroh , Sato Yumi , Yogo Hisanori , Sato Jiro , Ishikawa Teruhiko , Nishino Takashi
Published: July 2012

Background

Recent studies suggest advantages of muscle relaxants for facemask ventilation. However, direct effects of muscle relaxants on mask ventilation remain unclear because these studies did not control mechanical factors influencing ventilation. We tested a hypothesis that muscle relaxants, either rocuronium or succinylcholine, improve mask ventilation.

Methods

In anesthetized adult persons with normal upper airway anatomy, tidal volumes during facemask ventilation were measured while maintaining the neutral head and mandible positions and the airway pressures of a ventilator before and during muscle paralysis induced by either rocuronium (n=14) or succinylcholine (n=17). Tidal volumes of oral and nasal airway routes were separately measured with a custom-made oronasal portioning full facemask. Behavior of the oral airway was observed by an endoscope in six additional subjects receiving succinylcholine.

Results

Total, oral, and nasal tidal volumes did not significantly change at complete muscle paralysis with rocuronium. In contrast, succinylcholine significantly increased total tidal volumes at 60 s after its administration (mean±SD; 4.2±2.1 vs. 5.4±2.6 ml/kg, P=0.02) because of increases of ventilation through both airway routes. Abrupt tidal volume increase occurred more through oral airway route than nasal route. Dilation of the space at the isthmus of the fauces was endoscopically observed during pharyngeal fasciculation in all six subjects.

Conclusions

Rocuronium did not deteriorate facemask ventilation, and it was improved after succinylcholine administration in association with airway dilation during pharyngeal fasciculation. This effect continued to a lesser degree after resolution of the fasciculation.
Nebulized Lidocaine Prevents Airway Inflammation, Peribronchial Fibrosis, and Mucus Production in a Murine Model of Asthma
Authors: Serra Magda F. , Anjos-Valotta Edna A. , Olsen Priscilla C. , Couto Gina C. , Jurgilas Patricia B. , Cotias Amanda C. , Pão Camila R. , Ferreira Tatiana P. T. , Arantes Ana C. S. , Pires Ana L. A. , Cordeiro Renato S. B. , Silva Patricia M. R. , Martins Marco A.
Published: July 2012

Background

Evidence suggests that nebulized lidocaine is beneficial in asthma therapy, but to what extent and the mechanisms underlying this effect remain poorly understood. The aim of this study was to assess the impact of lidocaine treatment using a murine model of allergic asthma characterized by expression of pivotal features of the disease: inflammation, mucus production, and lung remodeling.

Methods

A/J mice sensitized with ovalbumin were treated with inhaled lidocaine or vehicle immediately after ovalbumin intranasal challenges. Lung function, total and differential leukocytes in bronchoalveolar lavage fluid, peribronchial eosinophil density, interleukin (IL)-4, IL-5 and eotaxin-1 levels, epithelial mucus, collagen, extracellular-matrix deposition, matrix metalloproteinase-9 activity, and GATA-3 expression were evaluated. Between five and eight animals per group were used.

Results

Inhaled lidocaine inhibited ovalbumin-induced airway hyperreactivity to methacholine, and accumulation of lymphocytes, neutrophils, and eosinophils in bronchoalveolar lavage fluid 24 h after the last allergen provocation. Lidocaine administration also prevented other pathophysiological changes triggered by ovalbumin in lung tissue, including peribronchial eosinophil and neutrophil infiltration, subepithelial fibrosis, increased content of collagen and mucus, matrix metalloproteinase-9 activity, and increased levels of IL-4, IL-5, IL-13, and eotaxin-1. Furthermore, inhaled lidocaine inhibited lung tissue GATA-3 expression in ovalbumin-challenged mice. We also demonstrated that lidocaine inhibited the expression of GATA-3 in ovalbumin-stimulated T cells in vitro.

Conclusions

Inhaled lidocaine prevents eosinophilic inflammation, overproduction of mucus, and peribronchial fibrosis in a murine model of asthma, and impaired airway hyperreactivity, possibly by inhibiting allergen-evoked GATA-3 expression and the subsequent up-regulation of proinflammatory cytokines and chemokines.
Who Is at Risk for Postdischarge Nausea and Vomiting after Ambulatory Surgery?
Authors: Apfel Christian C. , Philip Beverly K. , Cakmakkaya Ozlem S. , Shilling Ashley , Shi Yun-Ying , Leslie John B. , Allard Martin , Turan Alparslan , Windle Pamela , Odom-Forren Jan , Hooper Vallire D. , Radke Oliver C. , Ruiz Joseph , Kovac Anthony
Published: July 2012

Background

About one in four patients suffers from postoperative nausea and vomiting. Fortunately, risk scores have been developed to better manage this outcome in hospitalized patients, but there is currently no risk score for postdischarge nausea and vomiting (PDNV) in ambulatory surgical patients.

Methods

We conducted a prospective multicenter study of 2,170 adults undergoing general anesthesia at ambulatory surgery centers in the United States from 2007 to 2008. PDNV was assessed from discharge until the end of the second postoperative day. Logistic regression analysis was applied to a development dataset and the area under the receiver operating characteristic curve was calculated in a validation dataset.

Results

The overall incidence of PDNV was 37%. Logistic regression analysis of the development dataset (n=1,913) identified five independent predictors (odds ratio; 95% CI): female gender (1.54; 1.22 to 1.94), age less than 50 yr (2.17; 1.75 to 2.69), history of nausea and/or vomiting after previous anesthesia (1.50; 1.19 to 1.88), opioid administration in the postanesthesia care unit (1.93; 1.53 to 2.43), and nausea in the postanesthesia care unit (3.14; 2.44-4.04). In the validation dataset (n=257), zero, one, two, three, four, and five of these factors were associated with a PDNV incidence of 7%, 20%, 28%, 53%, 60%, and 89%, respectively, and an area under the receiver operating characteristic curve of 0.72 (0.69 to 0.73).

Conclusions

PDNV affects a substantial number of patients after ambulatory surgery. We developed and validated a simplified risk score to identify patients who would benefit from long-acting prophylactic antiemetics at discharge from the ambulatory care center.
Prognostic Assessment in Patients with Indolent B-Cell Lymphomas
Authors: Arcaini Luca , Rattotti Sara , Gotti Manuel , Luminari Stefano
Published: July 2012

Follicular lymphoma (FL) is an indolent lymphoma with long median survival. Many studies have been performed to build up prognostic scores potentially useful to identify patients with poorer outcome. In 2004, an international consortium coordinated by theInternational Follicular Lymphoma Prognostic Factor projectwas established and a new prognostic study was launched (FLIPI2) using progression-free survival (PFS) as main endpoint and integrating all the modern parameters prospectively collected. Low-grade non-Hodgkin lymphomas were once considered as a heterogenous group of lymphomas characterized by an indolent clinical course. Each entity is characterized by unique clinicobiologic features. Some studies have been focused on prognostic factors in single lymphoma subtypes, with the development of specific-entity scores based on retrospective series, for instance splenic marginal zone lymphoma (SMZL). A widely accepted prognostic tool for clinical usage for indolent non-follicular B-cell lymphomas is largely awaited. In this paper we summarized the current evidence regarding prognostic assessment of indolent follicular and non-follicular lymphomas.
Temporal Aspects of Surface Water Quality Variation Using Robust Statistical Tools
Authors: Mustapha Adamu , Aris Ahmad Zaharin , Ramli Mohammad Firuz , Juahir Hafizan
Published: July 2012

Robust statistical tools were applied on the water quality datasets with the aim of determining the most significance parameters and their contribution towards temporal water quality variation. Surface water samples were collected from four different sampling points during dry and wet seasons and analyzed for their physicochemical constituents. Discriminant analysis (DA) provided better results with great discriminatory ability by using five parameters with (P<0.05) for dry season affording more than 96% correct assignation and used five and six parameters for forward and backward stepwise in wet season data withP-value (P<0.05) affording 68.20% and 82%, respectively. Partial correlation results revealed that there are strong (rp=0.829) and moderate (rp=0.614) relationships between five-day biochemical oxygen demand (BOD5) and chemical oxygen demand (COD), total solids (TS) and dissolved solids (DS) controlling for the linear effect of nitrogen in the form of ammonia (NH3) and conductivity for dry and wet seasons, respectively. Multiple linear regression identified the contribution of each variable with significant valuesr= 0.988,R2= 0.976 andr= 0.970,R2= 0.942 (P<0.05) for dry and wet seasons, respectively. Repeated measuret-test confirmed that the surface water quality varies significantly between the seasons with significant valueP<0.05.
FAD2-DGAT2Genes Coexpressed in EndophyticAspergillus fumigatusDerived from Tung Oilseeds
Authors: Chen Yi-Cun , Wang Yang-Dong , Cui Qin-Qin , Zhan Zhi-Yong
Published: July 2012

Recent efforts to genetically engineer plants that contain fatty acid desaturases to produce valuable fatty acids have made only modest progress. Diacylglycerol acyltransferase 2 (DGAT2), which catalyzes the final step in triacylglycerol (TAG) assembly, might potentially regulate the biosynthesis of desired fatty acids in TAGs. To study the effects of tung tree (Vernicia fordii)vfDGAT2in channeling the desired fatty acids into TAG,vfDGAT2combined with the tung tree fatty acid desaturase-2 (vfFAD2) gene was co-introduced intoAspergillus fumigatus, an endophytic fungus isolated from healthy tung oilseed. Two transformants coexpressingvfFAD2andvfDGAT2showed a more than 6-fold increase in linoleic acid production compared to the originalA. fumigatusstrain, while a nearly 2-fold increase was found in the transformant expressing onlyvfFAD2. Our data suggest thatvfDGAT2plays a pivotal role in promoting linoleic acid accumulation in TAGs. This holds great promise for further genetic engineering aimed at producing valuable fatty acids.
A Neutral Risk on the Development of New-Onset Diabetes Mellitus (NODM) in Taiwanese Patients with Dyslipidaemia Treated with Fibrates
Authors: Lee Chien-Ying , Huang Kuang-Hua , Lin Chun-Che , Tsai Tung-Han , Shih Hung-Che
Published: July 2012

There are no data on the incidence of new-onset diabetes mellitus (NODM ) in nondiabetic dyslipidaemia patients treated with fibrates. The aim of our study was to clarify these issues, to investigate the relationship between NODM and fibrate and whether the fibrates lead to increased risk for developing NODM. A retrospective cohort study was conducted by analyzing the Longitudinal Health Insurance Database (LHID 2005) of the National Health Insurance Research Database (NHIRD) from 2005 to 2010 to investigate all fibrate prescriptions for patients with dyslipidaemia. We estimated the hazard ratios (HRs) of NODM associated with fibrate use. We identified 145 NODM patients among 3,815 dyslipidaemic patients in the database for the study period. The risk estimates for NODM for users of fenofibrate (HR 1.30; 95% CI 0.82, 2.05) and gemfibrozil (HR 0.771; 95% CI 0.49, 1.22) were not associated with an increased risk of developing NODM (P>0.05). Our results revealed that patients with dyslipidaemia who took fenofibrate and gemfibrozil had a neutral risk of NODM. The reasons may be associated with the fibrates have the properties that activate PPARαand in some cases also activated PPARγ, leading to showing a neutral risk of NODM.
Selection of theIn VitroCulture Media Influences mRNA Expression of Hedgehog Genes,Il-6,and Important Genes regarding Reactive Oxygen Species in Single Murine Preimplantation Embryos
Authors: Pfeifer N. , Baston-Büst D. M. , Hirchenhain J. , Friebe-Hoffmann U. , Rein D. T. , Krüssel J. S. , Hess A. P.
Published: July 2012

Background. The aim of this paper was to determine the influence of differentin vitroculture media on mRNA expression of Hedgehog genes,il-6,and important genes regarding reactive oxygen species in single mouse embryos.Methods. Reverse transcription of single embryos either culturedin vitrofrom day 0.5 until 3.5 (COOK’s Cleavage medium or Vitrolife’s G-1 PLUS medium) orin vivountil day 3.5post coitum. PCR was carried out forβ-actinfollowed by nested-PCR forshh, ihh, il-6, nox, gpx4, gpx1,andprdx2.Results. The number of murine blastocysts cultured in COOK medium which expressedil-6, gpx4, gpx1,andprdx2mRNA differed significantly compared to thein vivogroup. Except fornox, the mRNA profile of the Vitrolife media group embryos varied significantly from thein vivoones regarding the number of blastocysts expressing the mRNA ofshh, ihh, il-6, gpx4, gpx1andprdx2.Conclusions. The present study shows that differentin vitroculture media lead to different mRNA expression profiles during early development. Even the newly developedin vitroculture media are not able to mimic the female reproductive tract. The question of long-term consequences for children due to assisted reproduction techniques needs to be addressed in larger studies.