bluuebunny/crossref_metadata_2025 huggingface dataset:
Structure-based variable selection for survival data
Authors: Lagani Vincenzo , Tsamardinos Ioannis
Published: June 2010

Motivation: Variable selection is a typical approach used for molecular-signature and biomarker discovery; however, its application to survival data is often complicated by censored samples. We propose a new algorithm for variable selection suitable for the analysis of high-dimensional, right-censored data called Survival Max–Min Parents and Children (SMMPC). The algorithm is conceptually simple, scalable, based on the theory of Bayesian networks (BNs) and the Markov blanket and extends the corresponding algorithm (MMPC) for classification tasks. The selected variables have a structural interpretation: if T is the survival time (in general the time-to-event), SMMPC returns the variables adjacent to T in the BN representing the data distribution. The selected variables also have a causal interpretation that we discuss.

Results: We conduct an extensive empirical analysis of prototypical and state-of-the-art variable selection algorithms for survival data that are applicable to high-dimensional biological data. SMMPC selects on average the smallest variable subsets (less than a dozen per dataset), while statistically significantly outperforming all of the methods in the study returning a manageable number of genes that could be inspected by a human expert.

Availability: Matlab and R code are freely available from http://www.mensxmachina.org

Contact:  vlagani@ics.forth.gr

Supplementary information:  Supplementary data are available at Bioinformatics online.
Disruption of Two Defensive Signaling Pathways by a Viral RNA Silencing Suppressor
Authors: Lewsey Mathew G. , Murphy Alex M. , MacLean Daniel , Dalchau Neil , Westwood Jack H. , Macaulay Keith , Bennett Mark H. , Moulin Michael , Hanke David E. , Powell Glen , Smith Alison G. , Carr John P.
Published: June 2010

The Cucumber mosaic virus (CMV) 2b counter-defense protein disrupts plant antiviral mechanisms mediated by RNA silencing and salicylic acid (SA). We used microarrays to investigate defensive gene expression in 2b-transgenic Arabidopsis thaliana plants. Surprisingly, 2b inhibited expression of few SA-regulated genes and, in some instances, enhanced the effect of SA on certain genes. Strikingly, the 2b protein inhibited changes in the expression of 90% of genes regulated by jasmonic acid (JA). Consistent with this, infection of plants with CMV, but not the 2b gene-deletion mutant CMVΔ2b, strongly inhibited JA-inducible gene expression. JA levels were unaffected by infection with either CMV or CMVΔ2b. Although the CMV–Arabidopsis interaction is a compatible one, SA accumulation, usually considered to be an indicator of plant resistance, was increased in CMV-infected plants but not in CMVΔ2b-infected plants. Thus, the 2b protein inhibits JA signaling at a step downstream of JA biosynthesis but it primes induction of SA biosynthesis by another CMV gene product or by the process of infection itself. Like many plant viruses, CMV is aphid transmitted. JA is important in plant defense against insects. This raises the possibility that disruption of JA-mediated gene expression by the 2b protein may influence CMV transmission by aphids.
Nitric Oxide Participates in the Complex Interplay of Defense-Related Signaling Pathways Controlling Disease Resistance to Sclerotinia sclerotiorum in Arabidopsis thaliana
Authors: Perchepied Laure , Balagué Claudine , Riou Catherine , Claudel-Renard Clotilde , Rivière Nathalie , Grezes-Besset Bruno , Roby Dominique
Published: June 2010

Studies of the interaction between Arabidopsis thaliana and the necrotrophic fungal pathogen Sclerotinia sclerotiorum have been hampered by the extreme susceptibility of this model plant to the fungus. In addition, analyses of the plant defense response suggested the implication of a complex interplay of hormonal and signaling pathways. To get a deeper insight into this host-pathogen interaction, we first analyzed the natural variation in Arabidopsis for resistance to S. sclerotiorum. The results revealed a large variation of resistance and susceptibility in Arabidopsis, with some ecotypes, such as Ws-4, Col-0, and Rbz-1, being strongly resistant, and others, such as Shahdara, Ita-0, and Cvi-0, exhibiting an extreme susceptibility. The role of different signaling pathways in resistance was then determined by assessing the symptoms of mutants affected in the perception, production, or transduction of hormonal signals after inoculation with S. sclerotiorum. This analysis led to the conclusions that i) signaling of inducible defenses is predominantly mediated by jasmonic acid and abscisic acid, influenced by ethylene, and independent of salicylic acid; and ii) nitric oxide (NO) and reactive oxygen species are important signals required for plant resistance to S. sclerotiorum. Defense gene expression analysis supported the specific role of NO in defense activation.
Involvement of Salicylate and Jasmonate Signaling Pathways in Arabidopsis Interaction with Fusarium graminearum
Authors: Makandar Ragiba , Nalam Vamsi , Chaturvedi Ratnesh , Jeannotte Richard , Sparks Alexis A. , Shah Jyoti
Published: June 2010

Fusarium graminearum is the principal causative agent of Fusarium head blight (FHB), a devastating disease of wheat and barley. This fungus can also colonize Arabidopsis thaliana. Disease resistance was enhanced in transgenic wheat and Arabidopsis plants that constitutively overexpress the NONEXPRESSOR OF PATHOGENESIS-RELATED GENES 1 (NPR1) gene, which regulates salicylic acid (SA) signaling and modulates the activation of jasmonic acid (JA)-dependent defenses. Here, we provide several lines of evidence that reveal an important role for SA and JA signaling in Arabidopsis defense against F. graminearum. SA level was elevated in fungus-inoculated leaves, and SA application and biologically activated systemic acquired resistance enhanced resistance. Furthermore, the disruption of SA accumulation and signaling in the sid2 mutant and NahG transgenic plant, and the npr1 and wrky18 mutants, respectively, resulted in heightened susceptibility to this fungus in leaves and inflorescence. JA signaling was activated in parallel with SA signaling in the fungus-challenged plants. However, the hyperresistance of the JA pathway mutants opr3, coi1, and jar1 indicates that this pathway contributes to susceptibility. Genetic and biochemical experiments indicate that the JA pathway promotes disease by attenuating the activation of SA signaling in fungus-inoculated plants. However, the hypersusceptibility of the jar1 npr1 double mutant compared with the npr1 mutant suggests that JAR1 also contributes to defense, signifying a dichotomous role of JA and a JAR1-dependent mechanism in this interaction.
ClpXP Protease Regulates the Type III Secretion System of Dickeya dadantii 3937 and Is Essential for the Bacterial Virulence
Authors: Li Yan , Yamazaki Akihiro , Zou Lifang , Biddle Eulandria , Zeng Quan , Wang Yongjun , Lin Haiping , Wang Qi , Yang Ching-Hong
Published: June 2010

The type III secretion system (T3SS) is considered one of the major virulence factors in many bacterial pathogens. This report demonstrates that RssB, ClpXP, and RpoS play a role in T3SS regulation of Dickeya dadantii 3937. ClpP is a serine-type protease which associates with the ClpX chaperone to form a functional Clp proteolytic complex for degradation of proteins. With the assistance of recognition factor RssB, ClpXP degrades the RpoS sigma factor. RpoS positively regulates the expression of the rsmA gene encoding an RNA-binding regulatory protein. By interacting with the hrpL mRNA, RsmA reduces HrpL production and downregulates the T3SS genes in the HrpL regulon. In addition, ClpXP, RssB, and RpoS affect pectinolytic enzyme production in D. dadantii 3937, probably through RsmA. The ClpXP and RssB proteins are essential for bacterial virulence.
A Unique Glycine-Rich Motif at the N-terminal Region of Bamboo mosaic virus Coat Protein Is Required for Symptom Expression
Authors: Lan Ping , Yeh Wen-Bin , Tsai Chih-Wei , Lin Na-Sheng
Published: June 2010

The coat proteins (CP) of many plant viruses are multifunctional proteins. We used N-terminal sequencing and mass spectrometry/mass spectrometry analysis to identify a truncated form of the Bamboo mosaic virus (BaMV) CP missing the N-terminal 35 amino acids (N35). The N35 region is unique in the potexviruses by its containing a glycine-rich motif (GRM) not present in databases but highly conserved among BaMV isolates. Results from site-directed mutagenesis and deletion mutational analysis showed that loss of this region converted necrotic local lesions to chlorotic local lesions on Chenopodium quinoa leaves. Furthermore, this region is required for successful development of mosaic symptoms on Nicotiana benthamiana leaves but is dispensable for BaMV replication and cell-to-cell and long-distance movement as well as virion assembly. This unique GRM-containing region of BaMV CP may be a symptom determinant in specific hosts.
Expression Pattern Suggests a Role of MiR399 in the Regulation of the Cellular Response to Local Pi Increase During Arbuscular Mycorrhizal Symbiosis
Authors: Branscheid Anja , Sieh Daniela , Pant Bikram Datt , May Patrick , Devers Emanuel A. , Elkrog Anders , Schauser Leif , Scheible Wolf-Rüdiger , Krajinski Franziska
Published: June 2010

Many plants improve their phosphate (Pi) availability by forming mutualistic associations with arbuscular mycorrhizal (AM) fungi. Pi-repleted plants are much less colonized by AM fungi than Pi-depleted plants. This indicates a link between plant Pi signaling and AM development. MicroRNAs (miR) of the 399 family are systemic Pi-starvation signals important for maintenance of Pi homeostasis in Arabidopsis thaliana and might also qualify as signals regulating AM development in response to Pi availability. MiR399 could either represent the systemic low-Pi signal promoting or required for AM formation or they could act as counter players of systemic Pi-availability signals that suppress AM symbiosis. To test either of these assumptions, we analyzed the miR399 family in the AM-capable plant model Medicago truncatula and could experimentally confirm 10 novel MIR399 genes in this species. Pi-depleted plants showed increased expression of mature miR399 and multiple pri-miR399, and unexpectedly, levels of five of the 15 pri-miR399 species were higher in leaves of mycorrhizal plants than in leaves of nonmycorrhizal plants. Compared with nonmycorrhizal Pi-depleted roots, mycorrhizal roots of Pi-depleted M. truncatula and tobacco plants had increased Pi contents due to symbiotic Pi uptake but displayed higher mature miR399 levels. Expression levels of MtPho2 remained low and PHO2-dependent Pi-stress marker transcript levels remained high in these mycorrhizal roots. Hence, an AM symbiosis-related signal appears to increase miR399 expression and decrease PHO2 activity. MiR399 overexpression in tobacco suggested that miR399 alone is not sufficient to improve mycorrhizal colonization supporting the assumption that, in mycorrhizal roots, increased miR399 are necessary to keep the MtPho2 expression and activity low, which would otherwise increase in response to symbiotic Pi uptake.
Pseudomonas syringae Two-Component Response Regulator RhpR Regulates Promoters Carrying an Inverted Repeat Element
Authors: Deng Xin , Lan Lefu , Xiao Yanmei , Kennelly Megan , Zhou Jian-Min , Tang Xiaoyan
Published: June 2010

The two-component system RhpRS was identified in Pseudomonas syringae as a regulator of the genes encoding the type III secretion system and type III effector proteins (together called the T3 genes). In the absence of the sensor kinase RhpS, the response regulator RhpR represses the induction of the T3 gene regulatory cascade consisting of hrpRS, hrpL, and the T3 genes in a phosphorylation-dependent manner. The repressor activity of RhpR is inhibited by RhpS, which presumably acts as a phosphatase under the T3 gene inducing conditions. Here, we show that RhpR binds and induces its own promoter in a phosphorylation-dependent manner. Deletion and mutagenesis analyses revealed an inverted repeat (IR) element, GTATC-N6-GATAC, in the rhpR promoter that confers the RhpR-dependent induction. Computational search of the P. syringae genomes for the putative IR elements and Northern blot analysis of the genes with a putative IR element in the promoter region uncovered five genes that were upregulated and two genes that were downregulated in an RhpR-dependent manner. Two genes that were strongly induced by RhpR were assayed for the IR element activity in gene regulation and, in both cases, the IR element mediated the RhpR-dependent gene induction. Chromatin immunoprecipitation assays indicated that RhpR binds the promoters containing a putative IR element but not the hrpR and hrpL promoters that do not have an IR element, suggesting that RhpR indirectly regulates the transcriptional cascade of hrpRS, hrpL, and the T3 genes.
Transcriptome Analysis of the Barley–Deoxynivalenol Interaction: Evidence for a Role of Glutathione in Deoxynivalenol Detoxification
Authors: Gardiner Stephanie A. , Boddu Jayanand , Berthiller Franz , Hametner Christian , Stupar Robert M. , Adam Gerhard , Muehlbauer Gary J.
Published: June 2010

Trichothecenes are a major group of toxins produced by phytopathogenic fungi, including Fusarium graminearum. Trichothecenes inhibit protein synthesis in eukaryotic cells and are toxicologically relevant mycotoxins for humans and animals. Because they promote plant disease, the role of host responses to trichothecene accumulation is considered to be an important aspect of plant defense and resistance to fungal infection. Our overall objective was to examine the barley response to application of the type B trichothecene deoxynivalenol (DON). We found that DON is diluted by movement from the application site to acropetal and basipetal florets. A susceptible barley genotype converted DON to DON-3-O-glucoside, indicating that UDP-glucosyltransferases capable of detoxifying DON must exist in barley. RNA profiling of DON-treated barley spikes revealed strong upregulation of gene transcripts encoding ABC transporters, UDP-glucosyltransferases, cytochrome P450s, and glutathione-S-transferases. We noted that transcripts encoding cysteine synthases were dramatically induced by DON, and that toxin-sensitive yeast on glutathione- or cysteine-supplemented media or carrying a gene that encodes a cysteine biosynthetic enzyme exhibit DON resistance, suggesting that preventing glutathione depletion by increasing cysteine supply could play a role in ameliorating the impact of DON. Evidence for nonenzymatic formation of DON-glutathione adducts in vitro was found using both liquid chromatography–mass spectrometry and nuclear magnetic resonance analysis, indicating that the formation of DON-glutathione conjugates in vivo may reduce the impact of trichothecenes. Our results indicate that barley exhibits multiple defense mechanisms against trichothecenes.
Validation of a Candidate Deoxynivalenol-Inactivating UDP-Glucosyltransferase from Barley by Heterologous Expression in Yeast
Authors: Schweiger Wolfgang , Boddu Jayanand , Shin Sanghyun , Poppenberger Brigitte , Berthiller Franz , Lemmens Marc , Muehlbauer Gary J. , Adam Gerhard
Published: June 2010

Resistance to the virulence factor deoxynivalenol (DON) due to formation of DON-3-O-glucoside (D3G) is considered to be an important component of resistance against Fusarium spp. which produce this toxin. Multiple candidate UDP-glycosyltransferase (UGT) genes from different crop plants that are either induced by Fusarium spp. or differentially expressed in cultivars varying in Fusarium disease resistance have been described. However, UGT are encoded by a very large gene family in plants. The study of candidate plant UGT is highly warranted because of the potential relevance for developing Fusarium-spp.-resistant crops. We tested Arabidopsis thaliana genes closely related to a previously identified DON-glucosyltransferase gene by heterologous expression in yeast and showed that gene products with very high sequence similarity can have pronounced differences in detoxification capabilities. We also tested four candidate barley glucosyltransferases, which are highly DON inducible. Upon heterologous expression of full-length cDNAs, only one gene, HvUGT13248, conferred DON resistance. The conjugate D3G accumulated in the supernatant of DON-treated yeast transformants. We also present evidence that the product of the TaUGT3 gene recently proposed to encode a DON-detoxification enzyme of wheat does not protect yeast against DON.
Soybean Resistance to Field Populations of Heterodera glycines in Selected Geographic Areas
Authors: Faghihi Jamal , Donald Patricia A. , Noel Gregory , Welacky Tom W. , Ferris Virginia R.
Published: June 2010

Data were collected 2006 through 2008 from 527 soil samples to determine the current effectiveness of PI 88788 and other sources of Heterodera glycines resistance in three geographically separated areas of soybean production: Tennessee and Indiana/Illinois, USA, and Ontario, Canada. In Tennessee where PI 88788 source of resistance has been used since 1978, 93% of field populations reproduced on PI 88788 (≥10% of susceptible cultivar), and no HG Type 0 populations were found. In Indiana and Illinois, where resistance was used since the mid-1980s, from 56 to 88% of the populations reproduced on PI 88788 (≥10%). PI 548402 (Peking), PI 90763, and PI 437654 had low reproduction (≤10%) unlike Tennessee where 78% of the populations reproduced on PI 548402 (≥10%) and 93% reproduced on PI 90763 (≥10%). In Ontario, where cultivars with PI 88788 resistance were used after 1989, PI 88788 in 73% of the field populations had ≤10% reproduction. But 15% of Ontario populations reproduced on PI 548402 (≥10%) and 6% reproduced on PI 90763 (≥10%), two sources of resistance not generally present in commercial cultivars grown in Ontario.

Accepted for publication 9 March 2010. Published 26 April 2010.
First Report of Leaf Smut of Gaillardia × grandiflora Caused by Entyloma gaillardianum in North America
Authors: Glawe Dean A. , Barlow Tess , Koike Steven T.
Published: June 2010

In the summer of 2009, a leaf spot disease occurred on 100% of Gaillardia × grandiflora cv. Goblin in a commercial nursery in coastal Monterey Co., CA. Nearly all of the affected plants were unsalable. The causal agent was determined to be Entyloma gaillardianum based on morphological features, host, and ITS region. This species has not been reported previously from this host in North America.

Accepted for publication 16 March 2010. Published 28 April 2010.
The 8th I. E. Melhus Graduate Student Symposium: Forty-Five Years After Van der Plank, New Visions for the Future of Plant Disease Epidemiology
Authors: Nutter Forrest W.
Published: June 2010

One of the most prestigious events held during each Annual Meeting of the American Phytopathological Society (APS) is the Irving E. Melhus Graduate Student Symposium. This symposium features graduate students who are chosen, on a competitive basis, to present their thesis research results.

Published 26 May 2010.
Quantification of Temporal and Spatial Dynamics of Bean pod mottle virus at Different Spatial Scales
Authors: Byamukama E. , Robertson A. E. , Nutter F. W.
Published: June 2010

Bean pod mottle virus (BPMV) is the most prevalent virus infecting soybean (Glycine max) in the United States; however, the temporal and spatial dynamics in BPMV at varying spatial scales has not been elucidated. To quantify the temporal and spatial dynamics of BPMV at a field scale, a quadrat-based method was developed in which six soybean rows, each consisting of 30-cm-long quadrats, were established within soybean cv. NE3001 field plots (i.e., 150 quadrats per plot) in BPMV-inoculated and non-inoculated plots. Quadrats were sampled by selecting the youngest fully expanded leaflet from each of four plants within each quadrat beginning 25 days after planting, and continued at 8- to 11-day intervals until crop senescence. Leaf sap was extracted from each 4-leaflet (bulked) sample (from each quadrat), and tested for presence of the BPMV by ELISA. Quadrat position (plot, row, and quadrat number) and the date of sampling that each quadrat first tested positive for BPMV was recorded and mapped. The rate of BPMV incidence in 2006 ranged from 0.09 to 0.12 logits/day, indicating that BPMV incidence was doubling every 5.3 to 7.7 days in 2006. Doubling times for BPMV incidence in 2007 were slower, ranging from 17.3 to 34.7 days. Analysis of spatial patterns using ordinary runs revealed that BPMV-infected quadrats were predominantly clustered within both BPMV-inoculated and non-inoculated plots throughout both growing seasons. In addition to within field plot studies, a threeyear statewide disease survey (2005-2007) was conducted in Iowa to quantify county and field scale BPMV prevalence and incidence by systematically selecting 30 plants/soybean field (8 to 16 soybean fields per county). Leaf samples were then tested for BPMV by ELISA and county-level BPMV incidence maps were generated using ArcGIS software. End-of-season BPMV prevalence was 39/96 counties in 2005 (40%), 90/99 counties in 2006 (90.1%), and 74/99 counties in 2007 (74.7%). The incidence of BPMV within Iowa counties ranged from 0 to 100% and BPMV incidence significantly increased statewide from north to south. Spatial autocorrelation (dependence) analysis using Moran's I revealed clustering for BPMV incidence among Iowa counties, indicating that BPMV incidence among counties was not random. The elucidation of the within-field temporal and spatial dynamics of BPMV and the statewide geographic distribution of BPMV in Iowa has important implications with regards to sampling, plant disease forensics, BPMV management, and risk prediction of BPMV.

Accepted for publication 28 January 2010. Published 26 May 2010.
New Perspectives on the Epidemiology of Citrus Stubborn Disease in California Orchards
Authors: Mello Alexandre F. S. , Yokomi Raymond K. , Melcher Ulrich , Chen Jianchi , Civerolo Edwin , Wayadande Astri C. , Fletcher Jacqueline
Published: June 2010

Although citrus stubborn disease (CSD), caused by the phloem resident mollicute Spiroplasma citri, is a significant threat to California citrus industry, our knowledge of its epidemiology is mostly anecdotal. We optimized multiple pathogen-detection protocols, measured disease incidence in two plots of commercial California groves, assessed pathogen impact on fruit quality and yield, and evaluated genetic diversity among S. citri isolates. Fruit columellas and receptacles were more suitable than leaves or bark for bacterial cultivation. Using cultivation and S. citri-specific PCR for detection, the incidence of CSD in two orchards, respectively, ranged from 46 to 85% and 1 to 4%, depending on the sampling technique. Yield and quality of fruits produced by trees that were mildly or severely CSD-symptomatic were compared to those of S. citri-free trees in one California orchard in 2006 and 2007. These infected trees had reduced fruit quality and up to 32% lower yield relative to S. citri-free trees. Using RAPD markers to compare 35 S. citri isolates collected 20 years ago from the United States and Mediterranean region with 34 isolates recently collected from California, significant genetic diversity was identified but was not correlated with the time or location of collection. Our findings suggest that CSD incidence in the commercial groves evaluated could be as high as 85% and its impact on yield and fruit quality are significant.

Accepted for publication 1 March 2010. Published 26 May 2010.
Aflatoxin Contamination in Corn Differs Among Inoculation Techniques
Authors: Bruns H. Arnold , Abbas Hamed K.
Published: June 2010

Aflatoxin research in corn (Zea mays L.) usually requires application of inoculum of Aspergillus flavus to soil or plant ears. The pin-bar vs. side-needle or spray vs. solid material inoculations using A. flavus isolate F3W4 (NRRL 30798) were compared in 2004, 2006, and 2007 using three hybrids in two irrigated experiments each year at Stoneville, MS. Both were planted on a silty clay soil in randomized complete block designs with four replications of treatments. Mature ears inoculated by the pin-bar, side-needle, or spray methods were analyzed for aflatoxin. Ears from controls and solid material inoculum treatments were sampled for analysis at plot harvest. Pin-bar inoculation had more aflatoxin in 2004 (551.9 ng/g) and 2006 (305.8 ng/g) than side-needle inoculation (342.2 ng/g and 151.1 ng/g for 2004 and 2006, respectively), which was greater than controls (76.8 ng/g and 21.6 ng/g for 2004 and 2006, respectively). Solid material inoculation did not differ in aflatoxin from controls. Spraying produced the most aflatoxin (344.1 ng/g) only in 2004. Aflatoxin was low in 2007 when timely rainfall, irrigation, and no temperatures ≥ 35°C resulted in only the pin-bar (20.8 ng/g) and solid material (20.6 ng/g) treatments having > 2.0 ng/g of aflatoxin.

Accepted for publication 26 March 2010. Published 1 June 2010.
Arterial and Plethysmographic Waveform Analysis in Anesthetized Patients with Hypovolemia
Authors: Pizov Reuven , Eden Arieh , Bystritski Dmitri , Kalina Elena , Tamir Ada , Gelman Simon
Published: June 2010

Background

Respiratory-induced arterial and plethysmographic (pulse oximetry) waveform changes were shown to be good predictors of cardiac output response to increased preload. The aim of this study was to evaluate the reliability of arterial and plethysmographic waveform variables in patients with mild hypovolemia.

Methods

Patients undergoing autologous hemodilution were studied. After anesthesia induction, hemodilution was performed by withdrawing blood in steps of 2% of estimated circulating blood volume (ECBV), up to 20%. The patients who did not develop hypotension (systolic blood pressure < 80 mmHg) were studied. Arterial and plethysmographic waveforms were recorded and analyzed off-line at baseline and after each withdrawal of blood. Variations in arterial systolic and pulse pressure were analyzed using standard methods. Plethysmographic waveform variation and delta pulse oximetry plethysmography were determined by using pulse oximetry recordings.

Results

There were 33 study participants. Systolic blood pressure decreased by 11%, and heart rate increased from 73 to 76 beats/min after a 20% reduction of ECBV. Systolic pressure and pulse pressure variations increased (P < 0.005) after a 4% reduction of ECBV. The values of arterial pressure and pulse oximetry waveform variables almost doubled in value after a 20% reduction of ECBV. Systolic pressure variation was the most reliable variable during hypovolemia. Plethysmographic waveform variation increased significantly after a 6% reduction of ECBV and delta pulse oximetry plethysmography after an 8% reduction of ECBV.

Conclusions

Arterial and pulse oximetry respiratory-induced changes in waveform variables are reliable indicators of mild hypovolemia in anesthetized patients. The pulse oximetry plethysmographic waveforms accurately reflect arterial waveforms during more progressive hypovolemia.
Rapid Chemical Antagonism of Neuromuscular Blockade by l-Cysteine Adduction to and Inactivation of the Olefinic (Double-bonded) Isoquinolinium Diester Compounds Gantacurium (AV430A), CW 002, and CW 011
Authors: Savarese John J. , McGilvra Jeff D. , Sunaga Hiroshi , Belmont Matthew R. , Van Ornum Scott G. , Savard Peter M. , Heerdt Paul M.
Published: June 2010

Background

The ultra-short-acting neuromuscular blocker gantacurium is chemically degraded in vitro by rapid adduction of L-cysteine to its central olefinic double bond. Preliminary data have suggested that exogenous (intravenous) L-cysteine abolishes gantacurium blockade. Two new analogues of gantacurium (CW 002 and CW 011) have been synthesized to undergo slower L-cysteine adduction, yielding intermediate duration. L-cysteine adduction to and antagonism of these novel agents is further defined herein.

Methods

Comparative reaction half-time for L-cysteine adduction in vitro of the three compounds was determined by high-performance liquid chromatography. ED95 for twitch inhibition in monkeys under isoflurane was calculated, and duration at approximately 4-5x ED95 was correlated with reaction half-time for adduction. Speed of L-cysteine antagonism was contrasted with anticholinesterase reversal. Potencies of CW 002 and its adduction product were compared to provide a basis for L-cysteine antagonism.

Results

Rate of L-cysteine adduction in vitro (reaction half-time) was 11.4 and 13.7 min for CW 002 and CW 011 versus 0.2 min for gantacurium, and was inversely related to duration of block (P < 0.0001). CW 002 and CW 011 were 3x longer acting than gantacurium (28.1 and 33.3 min vs. 10.4 min), but only half the duration of cisatracurium. The adduct of CW 002 was approximately 70x less potent than CW 002. L-cysteine (10-50 mg/kg intravenously) given 1 min after approximately 4-5x ED95 doses of all the three compounds abolished block within 2-3 min.

Conclusions

L-cysteine adduction occurs at different rates by design in olefinic isoquinolinium diester neuromuscular blockers, yielding corresponding durations of action. Antagonism by exogenous L-cysteine is superior to anticholinesterases, inducing inactivation of the active molecules to restore function rapidly at any time.
Effects of Intrathecal Ketamine in the Neonatal Rat
Authors: Walker Suellen M. , Westin B. David , Deumens Ronald , Grafe Marjorie , Yaksh Tony L.
Published: June 2010

Background

Systemic ketamine can trigger apoptosis in the brain of rodents and primates during susceptible developmental periods. Clinically, spinally administered ketamine may improve the duration or quality of analgesia in children. Ketamine-induced spinal cord toxicity has been reported in adult animals but has not been systematically studied in early development.

Methods

In anesthetized rat pups, intrathecal ketamine was administered by lumbar percutaneous injection. Changes in mechanical withdrawal threshold evaluated dose-dependent antinociceptive and carrageenan-induced antihyperalgesic effects in rat pups at postnatal day (P) 3 and 21. After intrathecal injection of ketamine at P3, 7, or 21, spinal cords were examined for apoptosis (Fluoro-Jade C and activated caspase-3), histopathologic change, and glial responses (ionized calcium-binding adapter molecule 1 and glial fibrillary acid protein). After maximal doses of ketamine or saline at P3 or P21, sensory thresholds and gait analysis were evaluated at P35.

Results

Intrathecal injection of 3 mg/kg ketamine at P3 and 15 mg/kg at P21 reverses carrageenan-induced hyperalgesia. Baseline neuronal apoptosis in the spinal cord was greater at P3 than P7, predominantly in the dorsal horn. Intrathecal injection of 3-10 mg/kg ketamine in P3 pups (but not 15 mg/kg at P21) acutely increased apoptosis and microglial activation in the spinal cord and altered spinal function (reduced mechanical withdrawal threshold and altered static gait parameters) at P35.

Conclusions

Because acute pathology and long-term behavioral change occurred in the same dose range as antihyperalgesic effects, the therapeutic ratio of intrathecal ketamine is less than one in the neonatal rat. This measure facilitates comparison of the relative safety of spinally administered analgesic agents.
Tooth chipping can reveal the diet and bite forces of fossil hominins
Authors: Constantino Paul J. , Lee James J.-W. , Chai Herzl , Zipfel Bernhard , Ziscovici Charles , Lawn Brian R. , Lucas Peter W.
Published: June 2010

Mammalian tooth enamel is often chipped, providing clear evidence for localized contacts with large hard food objects. Here, we apply a simple fracture equation to estimate peak bite forces directly from chip size. Many fossil hominins exhibit antemortem chips on their posterior teeth, indicating their use of high bite forces. The inference that these species must have consumed large hard foods such as seeds is supported by the occurrence of similar chips among known modern-day seed predators such as orangutans and peccaries. The existence of tooth chip signatures also provides a way of identifying the consumption of rarely eaten foods that dental microwear and isotopic analysis are unlikely to detect.
Some sauropods raised their necks—evidence for high browsing in
Euhelopus zdanskyi
Authors: Christian Andreas
Published: June 2010

A very long neck that is apparently suitable for feeding at great heights is a characteristic feature of most sauropod dinosaurs. Yet, it remains controversial whether any sauropods actually raised their necks high. Recently, strong physiological arguments have been put forward against the idea of high-browsing sauropods, because of the very high blood pressure that appears to be inevitable when the head is located several metres above the heart. For the sauropod
Euhelopus zdanskyi
, however, biomechanical evidence clearly indicates high browsing. Energy expenditure owing to high browsing is compared with energy costs for walking a distance. It is demonstrated for
Euhelopus
as well as for the much larger
Brachiosaurus
that despite an increase in the metabolic rate, high browsing was worthwhile for a sauropod if resources were far apart.
Controlling the thickness of hollow polymeric microspheres prepared by electrohydrodynamic atomization
Authors: Chang Ming-Wei , Stride Eleanor , Edirisinghe Mohan
Published: June 2010

In this study, the ability to control the shell thickness of hollow polymeric microspheres prepared using electrohydrodynamic processing at ambient temperature was investigated. Polymethylsilsesquioxane (PMSQ) was used as a model material for the microsphere shell encapsulating a core of liquid perfluorohexane (PFH). The microspheres were characterized by Fourier transform infrared spectroscopy and optical and electron microscopy, and the effects of the processing parameters (flow-rate ratio, polymer concentration and applied voltage) on the mean microsphere diameter (
D
) and shell thickness (
t
) were determined. It was found that the mean diameters of the hollow microspheres could be controlled in the range from 310 to 1000 nm while the corresponding mean shell thickness varied from 40 to 95 nm. The results indicate that the ratio
D
:
t
varied with polymer concentration, with the largest value of approximately 10 achieved with a solution containing 18 wt% of the polymer, while the smallest value (6.6) was obtained at 36 wt%. For polymer concentrations above 63 wt%, hollow microspheres could not be generated, but instead PMSQ fibres encapsulating PFH liquid were obtained.
Bird migration flight altitudes studied by a network of operational weather radars
Authors: Dokter Adriaan M. , Liechti Felix , Stark Herbert , Delobbe Laurent , Tabary Pierre , Holleman Iwan
Published: June 2010

A fully automated method for the detection and quantification of bird migration was developed for operational C-band weather radar, measuring bird density, speed and direction as a function of altitude. These weather radar bird observations have been validated with data from a high-accuracy dedicated bird radar, which was stationed in the measurement volume of weather radar sites in The Netherlands, Belgium and France for a full migration season during autumn 2007 and spring 2008. We show that weather radar can extract near real-time bird density altitude profiles that closely correspond to the density profiles measured by dedicated bird radar. Doppler weather radar can thus be used as a reliable sensor for quantifying bird densities aloft in an operational setting, which—when extended to multiple radars—enables the mapping and continuous monitoring of bird migration flyways. By applying the automated method to a network of weather radars, we observed how mesoscale variability in weather conditions structured the timing and altitude profile of bird migration within single nights. Bird density altitude profiles were observed that consisted of multiple layers, which could be explained from the distinct wind conditions at different take-off sites. Consistently lower bird densities are recorded in The Netherlands compared with sites in France and eastern Belgium, which reveals some of the spatial extent of the dominant Scandinavian flyway over continental Europe.
A review of nanoparticle functionality and toxicity on the central nervous system
Authors: Yang Z. , Liu Z. W. , Allaker R. P. , Reip P. , Oxford J. , Ahmad Z. , Ren G.
Published: June 2010

Although nanoparticles have tremendous potential for a host of applications, their adverse effects on living cells have raised serious concerns recently for their use in the healthcare and consumer sectors. As regards the central nervous system (CNS), research data on nanoparticle interaction with neurons has provided evidence of both negative and positive effects. Maximal application dosage of nanoparticles in materials to provide applications such as antibacterial and antiviral functions is approximately 0.1–1.0 wt%. This concentration can be converted into a liquid phase release rate (leaching rate) depending upon the host or base materials used. For example, nanoparticulate silver (Ag) or copper oxide (CuO)-filled epoxy resin demonstrates much reduced release of the metal ions (Ag
+
or Cu
2+
) into their surrounding environment unless they are mechanically removed or aggravated. Subsequent to leaching effects and entry into living systems, nanoparticles can also cross through many other barriers, such as skin and the blood–brain barrier (BBB), and may also reach bodily organs. In such cases, their concentration or dosage in body fluids is considered to be well below the maximum drug toxicity test limit (10
−5
g ml
−1
) as determined in artificial cerebrospinal solution. As this is a rapidly evolving area and the use of such materials will continue to mature, so will their exposure to members of society. Hence, neurologists have equal interests in nanoparticle effects (positive functionality and negative toxicity) on human neuronal cells within the CNS, where the current research in this field will be highlighted and reviewed.
In silico
modelling of drug–polymer interactions for pharmaceutical formulations
Authors: Ahmad Samina , Johnston Blair F. , Mackay Simon P. , Schatzlein Andreas G. , Gellert Paul , Sengupta Durba , Uchegbu Ijeoma F.
Published: June 2010

Selecting polymers for drug encapsulation in pharmaceutical formulations is usually made after extensive trial and error experiments. To speed up excipient choice procedures, we have explored coarse-grained computer simulations (dissipative particle dynamics (DPD) and coarse-grained molecular dynamics using the MARTINI force field) of polymer–drug interactions to study the encapsulation of prednisolone (log
p
= 1.6), paracetamol (log
p
= 0.3) and isoniazid (log
p
= −1.1) in poly(
l
-lactic acid) (PLA) controlled release microspheres, as well as the encapsulation of propofol (log
p
= 4.1) in bioavailability enhancing quaternary ammonium palmitoyl glycol chitosan (GCPQ) micelles. Simulations have been compared with experimental data. DPD simulations, in good correlation with experimental data, correctly revealed that hydrophobic drugs (prednisolone and paracetamol) could be encapsulated within PLA microspheres and predicted the experimentally observed paracetamol encapsulation levels (5–8% of the initial drug level) in 50 mg ml
−1
PLA microspheres, but only when initial paracetamol levels exceeded 5 mg ml
−1
. However, the mesoscale technique was unable to model the hydrophilic drug (isoniazid) encapsulation (4–9% of the initial drug level) which was observed in experiments. Molecular dynamics simulations using the MARTINI force field indicated that the self-assembly of GCPQ is rapid, with propofol residing at the interface between micellar hydrophobic and hydrophilic groups, and that there is a heterogeneous distribution of propofol within the GCPQ micelle population. GCPQ–propofol experiments also revealed a population of relatively empty and drug-filled GCPQ particles.
Predictions of tumour morphological stability and evaluation against experimental observations
Authors: Pham Kara , Frieboes Hermann B. , Cristini Vittorio , Lowengrub John
Published: June 2010

The hallmark of malignant tumours is their spread into neighbouring tissue and metastasis to distant organs, which can lead to life threatening consequences. One of the defining characteristics of aggressive tumours is an unstable morphology, including the formation of invasive fingers and protrusions observed both
in vitro
and
in vivo
. In spite of extensive biological, clinical and modelling study and research at physical scales ranging from the molecular to the tissue, the driving dynamics of tumour invasiveness are not completely understood, partly because it is challenging to observe and study cancer as a multi-scale system. Mathematical modelling has been applied to provide further insights into these complex invasive and metastatic behaviours. Modelling a solid tumour as an incompressible fluid, we consider three possible constitutive relations to describe tumour growth, namely Darcy's law, Stokes' law and the combined Darcy–Stokes law. We study the tumour morphological stability described by each model and evaluate the consistency between theoretical model predictions and experimental data from
in vitro
three-dimensional multicellular tumour spheroids. The analysis reveals that the Stokes model is the most consistent with the experimental observations, and that it predicts our experimental tumour growth is marginally stable. We further show that it is feasible to extract parameter values from a limited set of data and create a self-consistent modelling framework that can be extended to the multi-scale study of cancer.
Biomechanical properties of single chondrocytes and chondrons determined by micromanipulation and finite-element modelling
Authors: Nguyen Bac V. , Wang Qi Guang , Kuiper Nicola J. , El Haj Alicia J. , Thomas Colin R. , Zhang Zhibing
Published: June 2010

A chondrocyte and its surrounding pericellular matrix (PCM) are defined as a chondron. Single chondrocytes and chondrons isolated from bovine articular cartilage were compressed by micromanipulation between two parallel surfaces in order to investigate their biomechanical properties and to discover the mechanical significance of the PCM. The force imposed on the cells was measured directly during compression to various deformations and then holding. When the nominal strain at the end of compression was 50 per cent, force relaxation showed that the cells were viscoelastic, but this viscoelasticity was generally insignificant when the nominal strain was 30 per cent or lower. The viscoelastic behaviour might be due to the mechanical response of the cell cytoskeleton and/or nucleus at higher deformations. A finite-element analysis was applied to simulate the experimental force-displacement/time data and to obtain mechanical property parameters of the chondrocytes and chondrons. Because of the large strains in the cells, a nonlinear elastic model was used for simulations of compression to 30 per cent nominal strain and a nonlinear viscoelastic model for 50 per cent. The elastic model yielded a Young's modulus of 14 ± 1 kPa (mean ± s.e.) for chondrocytes and 19 ± 2 kPa for chondrons, respectively. The viscoelastic model generated an instantaneous elastic modulus of 21 ± 3 and 27 ± 4 kPa, a long-term modulus of 9.3 ± 0.8 and 12 ± 1 kPa and an apparent viscosity of 2.8 ± 0.5 and 3.4 ± 0.6 kPa s for chondrocytes and chondrons, respectively. It was concluded that chondrons were generally stiffer and showed less viscoelastic behaviour than chondrocytes, and that the PCM significantly influenced the mechanical properties of the cells.
William Maddock Bayliss's therapy for wound shock
Authors: Van der Kloot William
Published: June 2010

During World War I, military surgeons discovered that patients die from wound shock because their blood pressure falls catastrophically. William Maddock Bayliss produced experimental shock by bleeding anaesthetized cats, which lowers their blood pressure. He restored pressure by infusing salt solution containing enough gum acacia to generate the colloid osmotic pressure ordinarily contributed by the plasma proteins. Ernest Henry Starling had demonstrated that as plasma flows through the capillaries the colloid osmotic pressure of its proteins retains water. From 1917 to 1919 Bayliss and Starling served on the Special Investigation Committee on Surgical Shock and Allied Conditions of the Medical Research Committee. Both gum-saline and blood transfusions were used successfully on wound-shocked soldiers, but we do not know how many were treated, and the effectiveness of whole blood in comparison with gum-saline was not ascertained. Today the colloid osmotic pressure in transfusion solutions is usually provided by dextran or human albumin. Vast quantities are used, but Bayliss's role in the development of this clever biophysical therapy has been almost forgotten.
Asymptotic formulae for implied volatility in the Heston model
Authors: Forde Martin , Jacquier Antoine , Mijatović Aleksandar
Published: June 2010

In this paper, we prove an approximate formula expressed in terms of elementary functions for the implied volatility in the Heston model. The formula consists of the constant and first-order terms in the large maturity expansion of the implied volatility function. The proof is based on saddlepoint methods and classical properties of holomorphic functions.
On certain sums over the non-trivial zeta zeroes
Authors: Coffey Mark W.
Published: June 2010

We study coefficients
b

n

, expressible as sums over the Li/Keiper constants
λ

j

, that contain information on the Riemann xi function. We present a number of relations for and representations of
b

n

. These include the expression of
b

n

as a sum over non-trivial zeroes of the Riemann zeta function, as well as integral representations. Conditional on the Riemann hypothesis, we provide the asymptotic form of

.
Hydrodynamic object recognition using pressure sensing
Authors: Bouffanais Roland , Weymouth Gabriel D. , Yue Dick K. P.
Published: June 2010

Hydrodynamic sensing is instrumental to fish and some amphibians. It also represents, for underwater vehicles, an alternative way of sensing the fluid environment when visual and acoustic sensing are limited. To assess the effectiveness of hydrodynamic sensing and gain insight into its capabilities and limitations, we investigated the forward and inverse problem of detection and identification, using the hydrodynamic pressure in the neighbourhood, of a stationary obstacle described using a general shape representation. Based on conformal mapping and a general normalization procedure, our obstacle representation accounts for all specific features of progressive perceptual hydrodynamic imaging reported experimentally. Size, location and shape are encoded separately. The shape representation rests upon an asymptotic series which embodies the progressive character of hydrodynamic imaging through pressure sensing. A dynamic filtering method is used to invert noisy nonlinear pressure signals for the shape parameters. The results highlight the dependence of the sensitivity of hydrodynamic sensing not only on the relative distance to the disturbance but also its bearing.