bluuebunny/crossref_metadata_2025 huggingface dataset:
Osmotrophy in modular Ediacara organisms
Authors: Laflamme Marc , Xiao Shuhai , Kowalewski Michał
Published: August 2009

The Ediacara biota include macroscopic, morphologically complex soft-bodied organisms that appear globally in the late Ediacaran Period (575–542 Ma). The physiology, feeding strategies, and functional morphology of the modular Ediacara organisms (rangeomorphs and erniettomorphs) remain debated but are critical for understanding their ecology and phylogeny. Their modular construction triggered numerous hypotheses concerning their likely feeding strategies, ranging from micro-to-macrophagus feeding to photoautotrophy to osmotrophy. Macrophagus feeding in rangeomorphs and erniettomorphs is inconsistent with their lack of oral openings, and photoautotrophy in rangeomorphs is contradicted by their habitats below the photic zone. Here, we combine theoretical models and empirical data to evaluate the feasibility of osmotrophy, which requires high surface area to volume (SA/V) ratios, as a primary feeding strategy of rangeomorphs and erniettomorphs. Although exclusively osmotrophic feeding in modern ecosystems is restricted to microscopic bacteria, this study suggests that (
i
) fractal branching of rangeomorph modules resulted in SA/V ratios comparable to those observed in modern osmotrophic bacteria, and (
ii
) rangeomorphs, and particularly erniettomorphs, could have achieved osmotrophic SA/V ratios similar to bacteria, provided their bodies included metabolically inert material. Thus, specific morphological adaptations observed in rangeomorphs and erniettomorphs may have represented strategies for overcoming physiological constraints that typically make osmotrophy prohibitive for macroscopic life forms. These results support the viability of osmotrophic feeding in rangeomorphs and erniettomorphs, help explain their taphonomic peculiarities, and point to the possible importance of earliest macroorganisms for cycling dissolved organic carbon that may have been present in abundance during Ediacaran times.
Discovery of Escherichia coli methionyl-tRNA synthetase mutants for efficient labeling of proteins with azidonorleucine in vivo
Authors: Tanrikulu I. Caglar , Schmitt Emmanuelle , Mechulam Yves , Goddard William A. , Tirrell David A.
Published: August 2009

Incorporation of noncanonical amino acids into cellular proteins often requires engineering new aminoacyl-tRNA synthetase activity into the cell. A screening strategy that relies on cell-surface display of reactive amino acid side-chains was used to identify a diverse set of methionyl-tRNA synthetase (MetRS) mutants that allow efficient incorporation of the methionine (Met) analog azidonorleucine (Anl). We demonstrate that the extent of cell-surface labeling in vivo is a good indicator of the rate of Anl activation by the MetRS variant harbored by the cell. By screening at low Anl concentrations in Met-supplemented media, MetRS variants with improved activities toward Anl and better discrimination against Met were identified.
Conversion of MDCK cell line to suspension culture by transfecting with human
siat7e
gene and its application for influenza virus production
Authors: Chu Chia , Lugovtsev Vladimir , Golding Hana , Betenbaugh Michael , Shiloach Joseph
Published: August 2009

MDCK cells are currently being considered as an alternative to embryonated eggs for influenza virus propagation and hemagglutinin (HA) production intended for vaccine manufacturing. MDCK cells were found suitable for the virus production but their inability to grow in suspension burdens the process of scale up and hence their production capability. Anchorage-dependent MDCK cells were converted to anchorage-independent cells, capable of growing in suspension as a result of transfection with the human
siat7e
gene (ST6GalNac V). This gene was previously identified as having an important role in cellular adhesion when the transcriptions of genes from anchorage-dependent and anchorage-independent HeLa cells were compared. Unlike the parental MDCK cells, the
siat7e
-expressing cells were capable of growing in shake flasks as suspension cultures, achieving maximum concentration of 7 × 10
5
cells/mL while keeping close to 100% viability throughout the growth phase. In production experiments, the
siat7e
-expressing cells were infected with the Influenza B/Victoria/504/2000 strain. It was determined that the cell-derived viruses retained similar antigenic properties as those obtained from egg-derived viruses and their nucleotide sequences were identical. The specific production of hemagglutinin (expressed in hemagglutination units per 10
6
cells) from the
siat7e
-expressing cells was approximately 20 times higher than the specific production from the parental MDCK cells. If this suspension process scales up, the production potential of HA from 10 L of
siat7e
-expressing cells at a concentration of 10
6
cells/mL would be equivalent to the amount of HA obtained from 10,000 embryonated eggs.
Endogenous nonneuronal modulators of synaptic transmission control cortical slow oscillations in vivo
Authors: Fellin Tommaso , Halassa Michael M. , Terunuma Miho , Succol Francesca , Takano Hajime , Frank Marcos , Moss Stephen J. , Haydon Philip G.
Published: August 2009

Gliotransmission, the release of molecules from astrocytes, regulates neuronal excitability and synaptic transmission in situ. Whether this process affects neuronal network activity in vivo is not known. Using a combination of astrocyte-specific molecular genetics, with in vivo electrophysiology and pharmacology, we determined that gliotransmission modulates cortical slow oscillations, a rhythm characterizing nonrapid eye movement sleep. Inhibition of gliotransmission by the expression of a dominant negative SNARE domain in astrocytes affected cortical slow oscillations, reducing the duration of neuronal depolarizations and causing prolonged hyperpolarizations. These network effects result from the astrocytic modulation of intracortical synaptic transmission at two sites: a hypofunction of postsynaptic NMDA receptors, and by reducing extracellular adenosine, a loss of tonic A1 receptor-mediated inhibition. These results demonstrate that rhythmic brain activity is generated by the coordinated action of the neuronal and glial networks.
Preventing the collapse of the Baltic cod stock through an ecosystem-based management approach
Authors: Lindegren Martin , Möllmann Christian , Nielsen Anders , Stenseth Nils C.
Published: August 2009

Worldwide a number of fish stocks have collapsed because of overfishing and climate-induced ecosystem changes. Developing ecosystem-based fisheries management (EBFM) to prevent these catastrophic events in the future requires ecological models incorporating both internal food-web dynamics and external drivers such as fishing and climate. Using a stochastic food-web model for a large marine ecosystem (i.e., the Baltic Sea) hosting a commercially important cod stock, we were able to reconstruct the history of the stock. Moreover we demonstrate that in hindsight the collapse could only have been avoidable by adapting fishing pressure to environmental conditions and food-web interactions. The modeling approach presented here represents a significant advance for EBFM, the application of which is important for sustainable resource management in the future.
Subcellular localization of Nox4 and regulation in diabetes
Authors: Block Karen , Gorin Yves , Abboud Hanna E.
Published: August 2009

Oxidative stress is implicated in human diseases. Some of the oxidative pathways are harbored in the mitochondria. NAD(P)H oxidases have been identified not only in phagocytic but also in somatic cells. Nox4 is the most ubiquitous of these oxidases and is a major source of reactive oxygen species (ROS) in many cell types and in kidney tissue of diabetic animals. We generated specific Nox4 antibodies, and found that Nox4 localizes to mitochondria. (
i
) Immunoblot analysis in cultured mesangial cells and kidney cortex revealed that Nox4 is present in crude mitochondria, in mitochondria-enriched heavy fractions, and in purified mitochondria; (
ii
) immunofluorescence confocal microscopy also revealed that Nox4 localizes with the mitochondrial marker Mitotracker; and (
iii
) the mitochondrial localization prediction program MitoProt indicated that the probability score for Nox4 is identical to mitochondrial protein cytochrome
c
oxidase subunit IV. We also show that in purified mitochondria, siRNA-mediated knockdown of Nox4 significantly reduces NADPH oxidase activity in pure mitochondria and blocks glucose-induced mitochondrial superoxide generation. In a rat model of diabetes, mitochondrial Nox4 expression is increased in kidney cortex. Our data provide evidence that a functional Nox4 is present and regulated in mitochondria, indicating the existence of a previously undescribed source of ROS in this organelle.
Nonlinear electrophoretic response yields a unique parameter for separation of biomolecules
Authors: Pel Joel , Broemeling David , Mai Laura , Poon Hau-Ling , Tropini Giorgia , Warren René L. , Holt Robert A. , Marziali Andre
Published: August 2009

We demonstrate a unique parameter for biomolecule separation that results from the nonlinear response of long, charged polymers to electrophoretic fields and apply it to extraction and concentration of nucleic acids from samples that perform poorly under conventional methods. Our method is based on superposition of synchronous, time-varying electrophoretic fields, which can generate net drift of charged molecules even when the time-averaged molecule displacement generated by each field individually is zero. Such drift can only occur for molecules, such as DNA, whose motive response to electrophoretic fields is nonlinear. Consequently, we are able to concentrate DNA while rejecting high concentrations of contaminants. We demonstrate one application of this method by extracting DNA from challenging samples originating in the Athabasca oil sands.
The BH4 domain of Bcl-2 inhibits ER calcium release and apoptosis by binding the regulatory and coupling domain of the IP3 receptor
Authors: Rong Yi-Ping , Bultynck Geert , Aromolaran Ademuyiwa S. , Zhong Fei , Parys Jan B. , De Smedt Humbert , Mignery Gregory A. , Roderick H. Llewelyn , Bootman Martin D. , Distelhorst Clark W.
Published: August 2009

Although the presence of a BH4 domain distinguishes the antiapoptotic protein Bcl-2 from its proapoptotic relatives, little is known about its function. BH4 deletion converts Bcl-2 into a proapoptotic protein, whereas a TAT-BH4 fusion peptide inhibits apoptosis and improves survival in models of disease due to accelerated apoptosis. Thus, the BH4 domain has antiapoptotic activity independent of full-length Bcl-2. Here we report that the BH4 domain mediates interaction of Bcl-2 with the inositol 1,4,5-trisphosphate (IP3) receptor, an IP3-gated Ca
2+
channel on the endoplasmic reticulum (ER). BH4 peptide binds to the regulatory and coupling domain of the IP3 receptor and inhibits IP3-dependent channel opening, Ca
2+
release from the ER, and Ca
2+
-mediated apoptosis. A peptide inhibitor of Bcl-2-IP3 receptor interaction prevents these BH4-mediated effects. By inhibiting proapoptotic Ca
2+
signals at their point of origin, the Bcl-2 BH4 domain has the facility to block diverse pathways through which Ca
2+
induces apoptosis.
Medial temporal lobe activity can distinguish between old and new stimuli independently of overt behavioral choice
Authors: Kirwan C. Brock , Shrager Yael , Squire Larry R.
Published: August 2009

We collected fMRI data and confidence ratings as participants performed a recognition memory task that intermixed recently studied words and new (non-studied) words. We first replicated a typical finding from such studies; namely, increasing activity in medial temporal lobe structures with increasing confidence in the old/new decision. Because there are greater proportions of old items at higher confidence levels, such activity could be related to the confidence ratings or to whether items are old or new. When activity associated with old and new items was analyzed separately, we found that activity in the hippocampus bilaterally, as well as in anterior parahippocampal gyrus, was associated with the actual old/new status of the items rather than to which items participants believed to be old. Accordingly, activity in the medial temporal lobe can be modulated by the old/new status of stimuli and does not always track the behavioral response.
Long-term retention of self-fertilization in a fish clade
Authors: Tatarenkov Andrey , Lima Sergio M. Q. , Taylor D. Scott , Avise John C.
Published: August 2009

Among vertebrate animals, only the mangrove rivulus (
Kryptolebias marmoratus
) was known to self-fertilize. Here, we use microsatellite analyses to document a high selfing rate (97%) in a related nominal species,
Kryptolebias ocellatus
, which likewise is androdioecious (populations consist of males and hermaphrodites). In contrast, we find no evidence of self-fertilization in
Kryptolebias caudomarginatus
(an androdioecious species closely related to the
marmoratus-ocellatus
clade) or in
Kryptolebias brasiliensis
(a dioecious outgroup). These findings indicate that the initiation of self-fertilization predated the origin of the
marmoratus-ocellatus
clade. From mitochondrial DNA sequences and microsatellite data, we document a substantial genetic distance between
Kryptolebias marmoratus
and
K. ocellatus
, implying that the selfing capacity has persisted in these fishes for at least several hundred thousand years.
Response–effect compatibility of finger–numeral configurations in arithmetical context
Authors: Badets Arnaud , Pesenti Mauro , Olivier Etienne
Published: August 2009

The present study aimed at testing, by means of a response–effect compatibility paradigm, whether finger–numeral representations derived from finger counting may underlie simple arithmetic problem solving in adults. Participants were asked to provide a verbal response to simple additions, which triggered the presentation of the correct (Experiment 1) or an incorrect (Experiment 2) response, displayed either as a configuration of fingers or as a series of rods. Answers were faster with finger configurations than with rods, and only when the finger configuration showed the correct result. These findings support the idea that, even in adults, simple arithmetic operations are still unconsciously underlain by finger–numeral representations.
Decomposing the emotional Stroop effect
Authors: Frings Christian , Englert Julia , Wentura Dirk , Bermeitinger Christina
Published: August 2009

The emotional Stroop effect refers to the phenomenon that participants are faster in responding to the ink colour of neutral than of negative word stimuli, possibly reflecting fast and automatic allocation of attention towards negative stimuli. However, this interpretation was challenged by McKenna and Sharma (2004) who found that the emotional Stroop effect reflected a generic slowdown after negative stimuli. In fact, they even found reversed effects in a design in which neutral stimuli more often followed negative stimuli and vice versa. Yet, besides reversing the emotional Stroop effect this contingency might in fact have counteracted the fast effect, which was usually interpreted as the emotional Stroop effect. To decompose the emotional Stroop effect we used a design in which the foregoing and the current valence were uncorrelated and in which the fast and slow effects could be computed independently from each other. We found evidence for both fast and slow effects and discuss the practical implications for researchers using the emotional Stroop task as a measurement and the theoretical implications for researchers interested in the underlying cognitive mechanisms that contribute to the emotional Stroop effect.
The Dictyostelium type V myosin MyoJ is responsible for the cortical association and motility of contractile vacuole membranes
Authors: Jung Goeh , Titus Margaret A. , Hammer John A.
Published: August 2009

The contractile vacuole (CV) complex in Dictyostelium is a tubulovesicular osmoregulatory organelle that exhibits extensive motility along the actin-rich cortex, providing a useful model for investigating myosin-dependent membrane transport. Here, we show that the type V myosin myoJ localizes to CV membranes and is required for efficient osmoregulation, the normal accumulation of CV membranes in the cortex, and the conversion of collapsed bladder membranes into outwardly radiating cortical CV tubules. Complementation of myoJ-null cells with a version of myoJ containing a shorter lever arm causes these radiating tubules to move at a slower speed, confirming myoJ's role in translocating CV membranes along the cortex. MyoJ-null cells also exhibit a dramatic concentration of CV membranes around the microtubule-organizing center. Consistently, we demonstrate that CV membranes also move bi-directionally on microtubules between the cortex and the centrosome. Therefore, myoJ cooperates with plus and minus end–directed microtubule motors to drive the normal distribution and dynamics of the CV complex in Dictyostelium.
Motor domain phosphorylation and regulation of the Drosophila kinesin 13, KLP10A
Authors: Mennella Vito , Tan Dong-Yan , Buster Daniel W. , Asenjo Ana B. , Rath Uttama , Ma Ao , Sosa Hernando J. , Sharp David J.
Published: August 2009

Microtubule (MT)-destabilizing kinesin 13s perform fundamental roles throughout the cell cycle. In this study, we show that the Drosophila melanogaster kinesin 13, KLP10A, is phosphorylated in vivo at a conserved serine (S573) positioned within the α-helix 5 of the motor domain. In vitro, a phosphomimic KLP10A S573E mutant displays a reduced capacity to depolymerize MTs but normal affinity for the MT lattice. In cells, replacement of endogenous KLP10A with KLP10A S573E dampens MT plus end dynamics throughout the cell cycle, whereas a nonphosphorylatable S573A mutant apparently enhances activity during mitosis. Electron microscopy suggests that KLP10A S573 phosphorylation alters its association with the MT lattice, whereas molecular dynamics simulations reveal how KLP10A phosphorylation can alter the kinesin–MT interface without changing important structural features within the motor’s core. Finally, we identify casein kinase 1α as a possible candidate for KLP10A phosphorylation. We propose a model in which phosphorylation of the KLP10A motor domain provides a regulatory switch controlling the time and place of MT depolymerization.
Bringing KASH under the SUN: the many faces of nucleo-cytoskeletal connections
Authors: Razafsky David , Hodzic Didier
Published: August 2009

The nucleus is the most prominent cellular organelle, and its sharp boundaries suggest the compartmentalization of the nucleoplasm from the cytoplasm. However, the recent identification of evolutionarily conserved linkers of the nucleoskeleton to the cytoskeleton (LINC) complexes, a family of macromolecular assemblies that span the double membrane of the nuclear envelope, reveals tight physical connections between the two compartments. Here, we review the structure and evolutionary conservation of SUN and KASH domain–containing proteins, whose interaction within the perinuclear space forms the “nuts and bolts” of LINC complexes. Moreover, we discuss the function of these complexes in nuclear, centrosomal, and chromosome dynamics, and their connection to human disease.
Type I interferon drives tumor necrosis factor–induced lethal shock
Authors: Huys Liesbeth , Van Hauwermeiren Filip , Dejager Lien , Dejonckheere Eline , Lienenklaus Stefan , Weiss Siegfried , Leclercq Georges , Libert Claude
Published: August 2009

Tumor necrosis factor (TNF) is reputed to have very powerful antitumor effects, but it is also a strong proinflammatory cytokine. Injection of TNF in humans and mice leads to a systemic inflammatory response syndrome with major effects on liver and bowels. TNF is also a central mediator in several inflammatory diseases. We report that type I interferons (IFNs) are essential mediators of the lethal response to TNF. Mice deficient in the IFN-α receptor 1 (IFNAR-1) or in IFN-β are remarkably resistant to TNF-induced hypothermia and death. After TNF injection, IFNAR-1−/− mice produced less IL-6, had less bowel damage, and had less apoptosis of enterocytes and hepatocytes compared with wild-type (WT) mice. Extensive gene expression analysis in livers of WT and IFNAR-1−/− mice revealed a large deficiency in the response to TNF in the knockout mice, especially of IFN-stimulated response element–dependent genes, many of which encode chemokines. In livers of IFNAR-1−/− mice, fewer infiltrating white blood cells (WBCs) were detected by immunohistochemistry. Deficiency of type I IFN signaling provided sufficient protection for potentially safer therapeutic use of TNF in tumor-bearing mice. Our data illustrate that type I IFNs act as essential mediators in TNF-induced lethal inflammatory shock, possibly by enhancing cell death and inducing chemokines and WBC infiltration in tissues.
Organization and Dynamics of theAspergillus nidulansGolgi during Apical Extension and Mitosis
Authors: Pantazopoulou Areti , Peñalva Miguel A.
Published: August 2009

Aspergillus nidulans hyphae grow exclusively by apical extension. Golgi equivalents (GEs) labeled with mRFP-tagged PHOSBPdomain form a markedly polarized, dynamic network of ring-shaped and fenestrated cisternae that remains intact during “closed” mitosis. mRFP-PHOSBPGEs advance associated with the growing apex where secretion predominates but do not undergo long-distance movement toward the tip that could account for their polarization. mRFP-PHOSBPGEs overlap with the trans-Golgi resident Sec7 but do not colocalize with also polarized accretions of the early Golgi marker GrhAGrh1-GFP, indicating that early and late Golgi membranes segregate spatially. AnSec23-GFP ER exit sites (ERES) are numerous, relatively static foci localizing across the entire cell. However, their density is greatest near the tip, correlating with predominance of early and trans-Golgi elements in this region. Whereas GrhA-GFP structures and ERES reach the apical dome, mRFP-PHOSBPGEs are excluded from this region, which contains the endosome dynein loading zone. After latrunculin-mediated F-actin disruption, mRFP-PHOSBPGEs fragment and, like AnSec23-GFP ERES, depolarize. Brefeldin A transiently collapses late and early GEs into distinct aggregates containing Sec7/mRFP-PHOSBPand GrhA-GFP, respectively, temporarily arresting apical extension. Rapid growth reinitiates after washout, correlating with reacquisition of the normal Golgi organization that, we conclude, is required for apical extension.
MISTRAL: a tool for energy-based multiple structural alignment of proteins
Authors: Micheletti Cristian , Orland Henri
Published: August 2009

Motivation: The steady growth of the number of available protein structures has constantly motivated the development of new algorithms for detecting structural correspondences in proteins. Detecting structural equivalences in two or more proteins is computationally demanding as it typically entails the exploration of the combinatorial space of all possible amino acid pairings in the parent proteins. The search is often aided by the introduction of various constraints such as considering protein fragments, rather than single amino acids, and/or seeking only sequential correspondences in the given proteins. An additional challenge is represented by the difficulty of associating to a given alignment, a reliable a priori measure of its statistical significance.

Results: Here, we present and discuss MISTRAL (Multiple STRuctural ALignment), a novel strategy for multiple protein alignment based on the minimization of an energy function over the low-dimensional space of the relative rotations and translations of the molecules. The energy minimization avoids combinatorial searches and returns pairwise alignment scores for which a reliable a priori statistical significance can be given.

Availability: MISTRAL is freely available for academic users as a standalone program and as a web service at http://ipht.cea.fr/protein.php.

Contact:  michelet@sissa.it

Supplementary information:  Supplementary data are available at Bioinformatics online.
In Vitro and In Vivo Antibacterial Activity of Punica granatum Peel Ethanol Extract against Salmonella
Authors: Choi Jang-Gi , Kang Ok-Hwa , Lee Young-Seob , Chae Hee-Sung , Oh You-Chang , Brice Obiang-Obounou , Kim Min-San , Sohn Dong-Hwan , Kim Hun-Soo , Park Hyun , Shin Dong-Won , Rho Jung-Rae , Kwon Dong-Yeul
Published: August 2009

Punica granatum is commonly used in Korea as a traditional medicine for the treatment of pathogenic bacteria. In this study, we investigated the in vitro and in vivo antimicrobial activity of P. granatum peel EtOH extract (PGPE) against 16 strains of Salmonella. The minimal inhibitory concentrations of PGPE were in the range of 62.5–1000 x03BCg mL-1. In addition, the in vivo antibacterial activity of the PGPE extract was examined in a S. typhimurium infection mouse model. Mice were initially infected with S. typhimurium and then with PGPE. The extract was found to have significant effects on mortality and the numbers of viable S. typhimurium recovered from feces. Although clinical signs and histological damage were rarely observed in the treated mice, the untreated controls showed signs of lethargy and histological damage in the liver and spleen. Taken together, the results of this study indicate that PGPE has the potential to provide an effective treatment for salmonellosis.
The Use of Humor in Serious Mental Illness: A Review
Authors: Gelkopf Marc
Published: August 2009

There is now a relatively good understanding of the broad range of direct and indirect effects of humor and laughter on perceptions, attitudes, judgments and emotions, which can potentially benefit the physical and psychological state. This article presents a review and discussion of the use of humor and laughter in treating people with serious mental illness, distinguishing between clinical papers on individual and group psychotherapy, and empirical research reports describing humor and laughter interventions. In spite of the exponential growth of the field over the last 30 years, I conclude that empirical studies are still lacking, the studies that do exist have major methodological shortcomings, and the field is in dire need of further investigation.
The Ayurveda Education in India: How Well Are the Graduates Exposed to Basic Clinical Skills?
Authors: Patwardhan Kishor , Gehlot Sangeeta , Singh Girish , Rathore H. C. S.
Published: August 2009

“Ayurveda” is an ancient system of healthcare that is native to India. At present, in India, there are more than 240 colleges that offer a graduate‐level degree (Bachelor of Ayurvedic Medicine and Surgery—BAMS) in Ayurveda. Even though the Central Council of Indian Medicine, the governing body that monitors the matters related to Ayurveda education, has imposed various educational norms and regulations, the standard of education has been a cause of concern in recent years. The mushrooming of substandard Ayurvedic colleges is the most important factor that is being held responsible for this kind of erosion in the standards. The present study is a mailed survey, which was carried out to evaluate the “Extent of exposure to basic clinical skills during BAMS course” as perceived by the sample groups of students and teachers drawn from 32 Ayurvedic educational institutions spread all over India. A methodically validated questionnaire was used as the tool in the study, to which 1022 participants responded. The study indicates that there are some serious flaws in the existing system of the graduate‐level Ayurveda education. Since the Ayurvedic graduates play an important role in the primary healthcare delivery system of the country, governing bodies are required to take necessary steps to ensure the adequate exposure of the students to basic clinical skills. Along with the strict implementation of all the regulatory norms during the process of recognition of the colleges, introducing some changes in the policy model may also be required to tackle the situation.
Septal rebound stretch reflects the functional substrate to cardiac resynchronization therapy and predicts volumetric and neurohormonal response
Authors: De Boeck Bart W.L. , Teske Arco J. , Meine Mathias , Leenders Geert E. , Cramer Maarten J. , Prinzen Frits W. , Doevendans Pieter A.
Published: August 2009

Aims

To develop a novel myocardial deformation index that is highly sensitive to the effect of cardiac resynchronization therapy (CRT) and that can be used to predict response to CRT.

Methods and results

Before and 6.5 ± 2.3 months after implantation of a CRT device, longitudinal shortening and stretch were timed and quantified by speckle tracking echocardiography in a cohort of 62 patients. Distinction was made between systolic total stretch (STS; all systolic stretch) and systolic rebound stretch (SRS; only systolic stretch following initial shortening). Systolic total stretch and SRS could be measured in all wall segments in 41 of 62 patients. Septal SRS quantification was possible in all 62 patients and was performed by a blinded observer. Cardiac resynchronization therapy reduced STS (−55 ± 30%) but reduced SRS (−77 ± 21%) significantly more (P < 0.01). The largest amount of baseline SRS and the largest reductions in SRS (−90 ± 22%) were found in the septum. Reductions in local SRS were paralleled by increases in local systolic shortening that were twice as large (r = 0.79), thereby strongly improving septal function. Baseline values of septal SRS correlated with reductions in left ventricular end‐systolic volume index (ΔLVESVi; r = 0.62) and brain‐type natriuretic peptide (BNP) (Δlog10BNP; r = 0.57). Septal SRS was an independent predictor of CRT response in linear regression analysis and predicted ΔLVESVi of ≥15% with a sensitivity and specificity of 81% at ROC analysis (areas under the curve 0.89 ± 0.04).

Conclusion

Septal rebound stretch appears to be a sensitive and practical diagnostic criterion to quantify the functional substrate amenable to CRT and to predict response.
Red blood cell distribution width predicts long‐term outcome regardless of anaemia status in acute heart failure patients
Authors: Pascual‐Figal Domingo A. , Bonaque Juan C. , Redondo Belen , Caro Cesar , Manzano‐Fernandez Sergio , Sánchez‐Mas Jesús , Garrido Iris P. , Valdes Mariano
Published: August 2009

Aims

To study the long‐term prognostic value of red blood cell distribution width (RDW) in patients hospitalized with acute heart failure (AHF) and to compare the value of this measurement with haemoglobin levels and anaemia status.

Methods and results

During a 2‐year period, we studied 628 consecutive patients (aged 71 years [interquartile range, IQR: 61–77], 68% male) hospitalized with AHF. Demographic, clinical, echocardiographic, and laboratory characteristics were registered at discharge and patients were closely followed‐up for 38.1 months [16.5–49.1]. Median RDW was 14.4% [13.5–15.5] and was higher among decedents (15.0% [13.8–16.1] vs. 14.2 [13.3–15.3], P < 0.001). After adjustment for other prognostic factors in a multivariable Cox proportional‐hazards model, RDW remained a significant predictor (P = 0.004, HR 1.072, 95% CI 1.023–1.124); whereas, haemoglobin or anaemia status did not add prognostic information. RDW levels above the median were associated with a significantly lower survival rate on long‐term follow‐up (log rank <0.001). These levels were predictive of death in anaemic patients (n = 263, P = 0.029) and especially in non‐anaemic patients (n = 365) (P < 0.001, HR 1.287, 95% CI 1.147–1.445), even after adjustment in the multivariable model.

Conclusion

Higher RDW levels at discharge were associated with a worse long‐term outcome, regardless of haemoglobin levels and anaemia status.
A fusion peptide directs enhanced systemic dystrophin exon skipping and functional restoration in dystrophin-deficient mdx mice
Authors: Yin HaiFang , Moulton Hong M , Betts Corinne , Seow Yiqi , Boutilier Jordan , Iverson Patrick L , Wood Matthew J A
Published: August 2009

Duchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene that abolish the synthesis of dystrophin protein. Antisense oligonucleotides (AOs) targeted to trigger excision of an exon bearing a mutant premature stop codon in the DMD transcript have been shown to skip the mutated exon and partially restore functional dystrophin protein in dystrophin-deficient mdx mice. To fully exploit the therapeutic potential of this method requires highly efficient systemic AO delivery to multiple muscle groups, to modify the disease process and restore muscle function. While systemic delivery of naked AOs in DMD animal models requires high doses and is of relatively poor efficiency, we and others have recently shown that short arginine-rich peptide-AO conjugates can dramatically improve in vivo DMD splice correction. Here we report for the first time that a chimeric fusion peptide (B-MSP-PMO) consisting of a muscle-targeting heptapeptide (MSP) fused to an arginine-rich cell-penetrating peptide (B-peptide) and conjugated to a morpholino oligomer (PMO) AO directs highly efficient systemic dystrophin splice correction in mdx mice. With very low systemic doses, we demonstrate that B-MSP-PMO restores high-level, uniform dystrophin protein expression in multiple peripheral muscle groups, yielding functional correction and improvement of the mdx dystrophic phenotype. Our data demonstrate proof-of-concept for this chimeric peptide approach in DMD splice correction therapy and is likely to have broad application.
Spatial prediction of demersal fish distributions: enhancing our understanding of species–environment relationships
Authors: Moore Cordelia H. , Harvey Euan S. , Van Niel Kimberly P.
Published: August 2009

Moore, C. H., Harvey, E. S., and Van Niel, K. P. 2009. Spatial prediction of demersal fish distributions: enhancing our understanding of species–environment relationships. – ICES Journal of Marine Science, 66: 2068–2075. We used species distribution modelling to identify key environmental variables influencing the spatial distribution of demersal fish and to assess the potential of these species–environment relationships to predict fish distributions accurately. In the past, predictive modelling of fish distributions has been limited, because detailed habitat maps of deeper water (>10 m) have not been available. However, recent advances in mapping deeper marine environments using hydroacoustic surveys have redressed this limitation. At Cape Howe Marine National Park in southeastern Australia, previously modelled benthic habitats based on hydroacoustic and towed video data were used to investigate the spatial ecology of demersal fish. To establish the influence of environmental variables on the distributions of this important group of marine fish, classification trees (CTs) and generalized additive models (GAMs) were developed for four demersal fish species. Contrasting advantages were observed between the two approaches. CTs provided greater explained variation for three of the four species and revealed a better ability to model species distributions with complex environmental interactions. However, the predictive accuracy of the GAMs was greater for three of the four species. Both these modelling techniques provided a detailed understanding of demersal fish distributions and landscape linkages and an accurate method for predicting species distributions across unsampled locations where continuous spatial benthic data are available. Information of this nature will permit more-targeted fisheries management and more-effective planning and monitoring of marine protected areas.
Tackling the diversity of sex determination
Authors: Wedekind Claus , Stelkens Rike B.
Published: August 2009

A workshop on ‘The evolution of sex determination systems’ was held at a remote place in the Swiss Alps from 17 to 20 June 2009. It brought together theoreticians and empiricists, the latter ranging from molecular geneticists to evolutionary ecologists, all trying to understand key aspects of sex determination. The topics discussed included the evolutionary origins of sex determination, the diversity of sex determination mechanisms in different taxa, and the transition from genotypic to environmental sex determination and vice versa.
The endosymbiontWolbachiaincreases insulin/IGF-like signalling inDrosophila
Authors: Ikeya Tomoatsu , Broughton Susan , Alic Nazif , Grandison Richard , Partridge Linda
Published: August 2009

Insulin/IGF-like signalling (IIS) is an evolutionarily conserved pathway that has diverse functions in multi-cellular organisms. Mutations that reduce IIS can have pleiotropic effects on growth, development, metabolic homeostasis, fecundity, stress resistance and lifespan. IIS is also modified by extrinsic factors. For instance, in the fruitflyDrosophila melanogaster, both nutrition and stress can alter the activity of the pathway. Here, we test experimentally the hypothesis that a widespread endosymbiont of arthropods,Wolbachia pipientis, can alter the degree to which mutations in genes encoding IIS components affect IIS and its resultant phenotypes.Wolbachiainfection, which is widespread inD. melanogasterin nature and has been estimated to infect 30 per cent of strains in the Bloomington stock centre, can affect broad aspects of insect physiology, particularly traits associated with reproduction. We measured a range of IIS-related phenotypes in flies ubiquitously mutant for IIS in the presence and absence ofWolbachia. We show that removal ofWolbachiafurther reduces IIS and hence enhances the mutant phenotypes, suggesting thatWolbachianormally acts to increase insulin signalling. This effect ofWolbachiainfection on IIS could have an evolutionary explanation, and has some implications for studies of IIS inDrosophilaand other organisms that harbour endosymbionts.
Evolution and emergence of novel human infections
Authors: Arinaminpathy N. , McLean A. R.
Published: August 2009

Some zoonotic pathogens cause sporadic infection in humans but rarely propagate further, while others have succeeded in overcoming the species barrier and becoming established in the human population. Adaptation, driven by selection pressure in human hosts, can play a significant role in allowing pathogens to cross this species barrier. Here we use a simple mathematical model to study potential epidemiological markers of adaptation. We ask: under what circumstances could ongoing adaptation be signalled by large clusters of human infection? If a pathogen has caused hundreds of cases but with little transmission, does this indicate that the species barrier cannot be crossed? Finally, how can case reports be monitored to detect an imminent emergence event? We distinguish evolutionary scenarios under which adaptation is likely to be signalled by large clusters of infection and under which emergence is likely to occur without any prior warning. Moreover, we show that a lack of transmission never rules out adaptability, regardless of how many zoonoses have occurred. Indeed, after the first 100 zoonotic cases, continuing sporadic zoonotic infections without onward, human-to-human transmission offer little extra information on pathogen adaptability. Finally, we present a simple method for monitoring outbreaks for signs of emergence and discuss public health implications.
No intracolonial nepotism during colony fissioning in honey bees
Authors: Rangel Juliana , Mattila Heather R. , Seeley Thomas D.
Published: August 2009

Most species of social insects have singly mated queens, but in some species each queen mates with numerous males to create a colony whose workers belong to multiple patrilines. This colony genetic structure creates a potential for intracolonial nepotism. One context with great potential for such nepotism arises in species, like honey bees, whose colonies reproduce by fissioning. During fissioning, workers might nepotistically choose between serving a young (sister) queen or the old (mother) queen, preferring the former if she is a full-sister but the latter if the young queen is only a half-sister. We examined three honeybee colonies that swarmed, and performed paternity analyses on the young (immature) queens and samples of workers who either stayed with the young queens in the nest or left with the mother queen in the swarm. For each colony, we checked whether patrilines represented by immature queens had higher proportions of staying workers than patrilines not represented by immature queens. We found no evidence of this. The absence of intracolonial nepotism during colony fissioning could be because the workers cannot discriminate between full-sister and half-sister queens when they are immature, or because the costs of behaving nepotistically outweigh the benefits.
Cuttlefish camouflage: context-dependent body pattern use during motion
Authors: Zylinski S. , Osorio D. , Shohet A. J.
Published: August 2009

It is virtually impossible to camouflage a moving target against a non-uniform background, but strategies have been proposed to reduce detection and targeting of movement. Best known is the idea that high contrast markings produce ‘motion dazzle’, which impairs judgement of speed and trajectory. The ability of the cuttlefishSepia officinalisto change its visual appearance allows us to compare the animal's choice of patterns during movement to the predictions of models of motion camouflage. We compare cuttlefish body patterns used during movement with those expressed when static on two background types; one of which promotes low-contrast mottle patterns and the other promotes high-contrast disruptive patterns. We find that the body pattern used during motion is context-specific and that high-contrast body pattern components are significantly reduced during movement. Thus, in our experimental conditions, cuttlefish do not use high contrast motion dazzle. It may be that, in addition to being inherently conspicuous during movement, moving high-contrast patterns will attract attention because moving particles in coastal waters tend to be of small size and of low relative contrast.
Behaviour and kinematics of continuous ram filtration in bowhead whales (Balaena mysticetus)
Authors: Simon Malene , Johnson Mark , Tyack Peter , Madsen Peter T.
Published: August 2009

Balaenid whales perform long breath-hold foraging dives despite a high drag from their ram filtration of zooplankton. To maximize the volume of prey acquired in a dive with limited oxygen supplies, balaenids must either filter feed only occasionally when prey density is particularly high, or they must swim at slow speeds while filtering to reduce drag and oxygen consumption. Using digital tags with three-axis accelerometers, we studied bowhead whales feeding off West Greenland and present here, to our knowledge, the first detailed data on the kinematics and swimming behaviour of a balaenid whale filter feeding at depth. Bowhead whales employ a continuous fluking gait throughout the bottom phase of foraging dives, moving at very slow speeds (less than 1 m s−1), allowing them to filter feed continuously at depth. Despite the slow speeds, the large mouth aperture provides a water filtration rate of approximately 3 m3s−1, amounting to some 2000 tonnes of water and prey filtered per dive. We conclude that a food niche of dense, slow-moving zooplankton prey has led balaenids to evolve locomotor and filtering systems adapted to work against a high drag at swimming speeds of less than 0.07 body length s−1using a continuous fluking gait very different from that of nekton-feeding, aquatic predators.
Synergistic antiproliferative effect of mTOR inhibitors in combination with 5‐fluorouracil in scirrhous gastric cancer
Authors: Matsuzaki Taro , Yashiro Masakazu , Kaizaki Ryoji , Yasuda Koichi , Doi Yosuke , Sawada Tetsuji , Ohira Masaichi , Hirakawa Kosei
Published: August 2009

The aim of this study is to clarify the benefit of combination chemotherapy in gastric cancer based on a cell‐signal inhibitor and an anticancer drug. Two scirrhous gastric cancer cell lines and two non‐scirrhous gastric cancer cell lines were used. Five anticancer drugs (5‐fluorouracil [5FU], paclitaxel, oxaliplatin, irinotecan, and gemcitabine) and four cell‐signal inhibitors, mammalian target of rapamycin (mTOR) inhibitor, glycogen synthase kinase 3β, p38αβMAPK, and cyclin‐dependent kinase, were used. The proliferation of cancer cells was examined by MTT assay and in vivo study. The apoptosis of cancer cells and the expression of apoptosis‐related molecules were examined by flow cytometry, real‐time PCR, and immunostaining. mTOR inhibitors with 5FU showed a synergistic antiproliferative effect in scirrhous gastric cancer, whereas the other signal inhibitors showed no synergistic effect with any anticancer drugs. mTOR inhibitor decreased the IC50 of 5FU and increased the apoptosis rate in scirrhous gastric cancer cells, but not in non‐scirrhous gastric cancer cells. The pan‐caspase inhibitor, zVAD‐fmk, inhibits apoptosis induced in combination with 5FU and mTOR inhibitor. mTOR inhibitor decreased dihydropyrimidine dehydrogenase, thymidylatesynthase, and bcl‐2expression, and increased caspase‐3 and p21 expression of scirrhous gastric cancer cells, but did not affect those of non‐scirrhous gastric cancer cells. In an in vivo study, mTOR inhibitor significantly enhanced the therapeutic efficacy of S1, an analog of 5FU. These findings suggest that mTOR inhibitor interacts with 5FU in a synergistic manner in scirrhous gastric cancer cells by the activation of the apoptosis signal. Therefore, mTOR inhibitor is a promising therapeutic agent in combination with 5FU in scirrhous gastric cancer. (Cancer Sci 2009; 100: 2402–2410)
αB‐crystallin: A novel p53‐target gene required for p53‐dependent apoptosis
Authors: Watanabe Gou , Kato Shunsuke , Nakata Hideyuki , Ishida Takanori , Ohuchi Noriaki , Ishioka Chikashi
Published: August 2009

The p53 protein is a transcription factor that trans‐activates various genes in response to DNA‐damaging stress. To search for new p53‐target genes, we applied a cDNA microarray system using two independent p53‐inducible cell lines, followed by in silico analysis to detect p53 response elements. Here, we report on crystallin alpha B gene (CRYAB), which encodes αB‐crystallin, and is one of the genes directly trans‐activated by p53. We confirmed it is directly transcribed by p53 using promoter analysis, deletion reporter assay, ChIP assay and EMSA. αB‐crystallin is also upregulated in a p53‐dependent manner and binds to the DNA‐binding domain of p53. Overexpression of αB‐crystallin increased p53 protein and, in contrast, repression of αB‐crystallin decreased p53 protein. Interestingly, both overexpression and repression of αB‐crystallin reduced p53‐dependent apoptosis. In conclusion, we identified that αB‐crystallin was a novel p53‐target gene and required for p53‐dependent apoptosis using two independent p53‐inducible cell lines. This is the first report associating p53 directly with a heat shock protein through trans‐activation and physical interaction. (Cancer Sci 2009; 100: 2368–2375)