bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Different pH Criteria on Dual‐sensor pH Monitoring in the Evaluation of Supraesophageal Gastric Reflux in Children
Authors: Chiou Eric , Rosen Rachel , Nurko Samuel
Published: January 2011

Background and Aim:

Existing tests for supraesophageal gastric reflux (SEGR) that focus on pH drops <4 in the proximal esophagus have had limited sensitivity and specificity. The aim of the present study was to evaluate the effect of newly proposed pH criteria on SEGR detection.

Patients and Methods:

Twenty‐four‐hour dual‐sensor pH tracings of 32 patients were reviewed. Proximal esophageal pH data were evaluated according to the conventional definition of pH drop <4 and 2 proposed definitions: pH drop <5.5 while upright and <5.0 while supine and pH drop of >10% from a running baseline. For each potential SEGR event, the preceding 1‐minute window was examined for corresponding distal acid reflux.

Results:

Of the 542 distal acid reflux events detected, 200 were associated with a proximal pH drop <4; this number increased to 295 using the definition of proximal pH drop <5.5 (upright)/<5.0 (supine) and 301 using the definition of proximal pH drop >10%. A proportion of proximal events, however, was not associated with distal acid reflux: 21 of 200 (10.5%) proximal pH <4 events, 119 of 414 (29%) proximal pH <5.5 (upright)/<5.0 (supine) events, and 272 of 573 (47%) proximal pH drop >10% events lacked a preceding or simultaneous drop in distal pH <4.

Conclusions:

Although the use of more liberal pH criteria increased the diagnostic yield for SEGR events with dual‐sensor monitoring, a significant proportion of proximal pH events did not correlate with distal acid reflux. These events could represent either false‐positive measurements or association with weakly acid reflux.
Early Increases in Concentrations of Total, LDL, and HDL Cholesterol in HIV‐infected Children Following New Exposure to Antiretroviral Therapy
Authors: Sztam Kevin A , Jiang Hongyu , Jurgrau Andrea , Deckelbaum Richard J , Foca Marc D
Published: January 2011

Antiretroviral therapy (ART) is associated with dyslipidemia and cardiovascular disease in adults infected with HIV. For children perinatally infected with HIV, ART exposure is lifelong and early‐onset dyslipidemia could have significant long‐term effects. We examined cholesterol levels in children during the first year after exposure to a new ART regimen (initiation or switch). In 52 children, total cholesterol increased by 30.5 and 43 mg/dL at 6 and 12 months, respectively (P < 0.001). Low‐density lipoprotein cholesterol made the largest contribution, but high‐density lipoprotein cholesterol also increased within months of therapy alteration. Early identification of these children and intervention could mediate potential increased risk for future cardiovascular disease.
Frontiers of marine science
Authors: Webb Thomas J. , Poloczanska Elvira S.
Published: January 2011

On 9–13 October 2010 early career scientists from the UK and Australia across marine research fields were given the opportunity to come together in Perth, Australia to discuss the frontiers of marine research and exchange ideas.
The fluid dynamics of swimming by jumping in copepods
Authors: Jiang Houshuo , Kiørboe Thomas
Published: January 2011

Copepods swim either continuously by vibrating their feeding appendages or erratically by repeatedly beating their swimming legs, resulting in a series of small jumps. The two swimming modes generate different hydrodynamic disturbances and therefore expose the swimmers differently to rheotactic predators. We developed an impulsive stresslet model to quantify the jump-imposed flow disturbance. The predicted flow consists of two counter-rotating viscous vortex rings of similar intensity, one in the wake and one around the body of the copepod. We showed that the entire jumping flow is spatially limited and temporally ephemeral owing to jump-impulsiveness and viscous decay. In contrast, continuous steady swimming generates two well-extended long-lasting momentum jets both in front of and behind the swimmer, as suggested by the well-known steady stresslet model. Based on the observed jump-swimming kinematics of a small copepod
Oithona davisae
, we further showed that jump-swimming produces a hydrodynamic disturbance with much smaller spatial extension and shorter temporal duration than that produced by a same-size copepod cruising steadily at the same average translating velocity. Hence, small copepods in jump-swimming are in general much less detectable by rheotactic predators. The present impulsive stresslet model improves a previously published impulsive Stokeslet model that applies only to the wake vortex.
Mechanisms of fluid production in smooth adhesive pads of insects
Authors: Dirks Jan-Henning , Federle Walter
Published: January 2011

Insect adhesion is mediated by thin fluid films secreted into the contact zone. As the amount of fluid affects adhesive forces, a control of secretion appears probable. Here, we quantify for the first time the rate of fluid secretion in adhesive pads of cockroaches and stick insects. The volume of footprints deposited during consecutive press-downs decreased exponentially and approached a non-zero steady state, demonstrating the presence of a storage volume. We estimated its size and the influx rate into it from a simple compartmental model. Influx was independent of step frequency. Fluid-depleted pads recovered maximal footprint volumes within 15 min. Pads in stationary contact accumulated fluid along the perimeter of the contact zone. The initial fluid build-up slowed down, suggesting that flow is driven by negative Laplace pressure. Freely climbing stick insects left hardly any traceable footprints, suggesting that they save secretion by minimizing contact area or by recovering fluid during detachment. However, even the highest fluid production rates observed incur only small biosynthesis costs, representing less than 1 per cent of the resting metabolic rate. Our results show that fluid secretion in insect wet adhesive systems relies on simple physical principles, allowing for passive control of fluid volume within the contact zone.
Contemporary morphological diversification of passerine birds introduced to the Hawaiian archipelago
Authors: Mathys Blake A. , Lockwood Julie L.
Published: January 2011

Species that have been introduced to islands experience novel and strong selection pressures after establishment. There is evidence that exotic species diverge from their native source populations; further, a few studies have demonstrated adaptive divergence across multiple exotic populations of a single species. Exotic birds provide a good study system, as they have been introduced to many locations worldwide, and we often know details concerning the propagule origin, time of introduction, and dynamics of establishment and dispersal within the introduced range. These data make them especially conducive to the examination of contemporary evolution. Island faunas have received intense scrutiny, therefore we have expectations concerning the patterns of diversification for exotic species. We examine six passerine bird species that were introduced to the Hawaiian archipelago less than 150 years ago. We find that five of these show morphological divergence among islands from the time since they were established. We demonstrate that some of this divergence cannot be accounted for by genetic drift, and therefore we must consider adaptive evolution to explain it. We also evaluate evolutionary divergence rates and find that these species are diverging at similar rates to those found in published studies of contemporary evolution in native species.
Local sleep homeostasis in the avian brain: convergence of sleep function in mammals and birds?
Authors: Lesku John A. , Vyssotski Alexei L. , Martinez-Gonzalez Dolores , Wilzeck Christiane , Rattenborg Niels C.
Published: January 2011

The function of the brain activity that defines slow wave sleep (SWS) and rapid eye movement (REM) sleep in mammals is unknown. During SWS, the level of electroencephalogram slow wave activity (SWA or 0.5–4.5 Hz power density) increases and decreases as a function of prior time spent awake and asleep, respectively. Such dynamics occur in response to waking brain use, as SWA increases locally in brain regions used more extensively during prior wakefulness. Thus, SWA is thought to reflect homeostatically regulated processes potentially tied to maintaining optimal brain functioning. Interestingly, birds also engage in SWS and REM sleep, a similarity that arose via convergent evolution, as sleeping reptiles and amphibians do not show similar brain activity. Although birds deprived of sleep show global increases in SWA during subsequent sleep, it is unclear whether avian sleep is likewise regulated locally. Here, we provide, to our knowledge, the first electrophysiological evidence for local sleep homeostasis in the avian brain. After staying awake watching David Attenborough's
The Life of Birds
with only one eye, SWA and the slope of slow waves (a purported marker of synaptic strength) increased only in the hyperpallium—a primary visual processing region—neurologically connected to the stimulated eye. Asymmetries were specific to the hyperpallium, as the non-visual mesopallium showed a symmetric increase in SWA and wave slope. Thus, hypotheses for the function of mammalian SWS that rely on local sleep homeostasis may apply also to birds.
Tracking leatherback turtles from the world's largest rookery: assessing threats across the South Atlantic
Authors: Witt Matthew J. , Augowet Bonguno Eric , Broderick Annette C. , Coyne Michael S. , Formia Angela , Gibudi Alain , Mounguengui Mounguengui Gil Avery , Moussounda Carine , NSafou Monique , Nougessono Solange , Parnell Richard J. , Sounguet Guy-Philippe , Verhage Sebastian , Godley Brendan J.
Published: January 2011

Despite extensive work carried out on leatherback turtles (
Dermochelys coriacea
) in the North Atlantic and Indo-Pacific, very little is known of the at-sea distribution of this species in the South Atlantic, where the world's largest population nests in Gabon (central Africa). This paucity of data is of marked concern given the pace of industrialization in fisheries with demonstrable marine turtle bycatch in African/Latin American waters. We tracked the movements of 25 adult female leatherback turtles obtaining a range of fundamental and applied insights, including indications for methodological advancement. Individuals could be assigned to one of three dispersal strategies, moving to (i) habitats of the equatorial Atlantic, (ii) temperate habitats off South America or (iii) temperate habitats off southern Africa. While occupying regions with high surface chlorophyll concentrations, these strategies exposed turtles to some of the world's highest levels of longline fishing effort, in addition to areas with coastal gillnet fisheries. Satellite tracking highlighted that at least 11 nations should be involved in the conservation of this species in addition to those with distant fishing fleets. The majority of tracking days were, however, spent in the high seas, where effective implementation of conservation efforts is complex to achieve.
Heritability and adaptive significance of the number of egg-dummies in the cichlid fish
Astatotilapia burtoni
Authors: Lehtonen Topi K. , Meyer Axel
Published: January 2011

Cichlid fishes are a textbook example of rapid speciation and exuberant diversity—this applies especially to haplochromines, a lineage with approximately 1800 species. Haplochromine males uniquely possess oval, bright spots on their anal fin, called ‘egg-spots’ or ‘egg-dummies’. These are presumed to be an evolutionary key innovation that contributed to the tribe's evolutionary success. Egg-spots have been proposed to mimic the ova of the mouthbrooding females of the corresponding species, contribute to fertilization success and even facilitate species recognition. Interestingly, egg-spot number varies extensively not only between species, but also within some populations. This high degree of intraspecific variation may appear to be counterintuitive since selection might be expected to act to stabilize traits that are correlated with fitness measures. We addressed this ‘paradox’ experimentally, and found that in the haplochromine cichlid
Astatotilapia burtoni
, the number of egg-spots was related to male age, body condition and dominance status. Intriguingly, the egg-spot number also had a high heritable component (narrow sense heritability of 0.5). These results suggest that the function of egg-spots might have less to do with fertilization success or species recognition, but rather relate to mate choice and/or male–male competition, helping to explain the high variability in this important trait.
Dopamine in
Drosophila
: setting arousal thresholds in a miniature brain
Authors: Van Swinderen Bruno , Andretic Rozi
Published: January 2011

In mammals, the neurotransmitter dopamine (DA) modulates a variety of behaviours, although DA function is mostly associated with motor control and reward. In insects such as the fruitfly,
Drosophila melanogaster
, DA also modulates a wide array of behaviours, ranging from sleep and locomotion to courtship and learning. How can a single molecule play so many different roles? Adaptive changes within the DA system, anatomical specificity of action and effects on a variety of behaviours highlight the remarkable versatility of this neurotransmitter. Recent genetic and pharmacological manipulations of DA signalling in
Drosophila
have launched a surfeit of stories—each arguing for modulation of some aspect of the fly's waking (and sleeping) life. Although these stories often seem distinct and unrelated, there are some unifying themes underlying DA function and arousal states in this insect model. One of the central roles played by DA may involve perceptual suppression, a necessary component of both sleep and selective attention.
Gene inactivation and its implications for annotation in the era of personal genomics
Authors: Balasubramanian Suganthi , Habegger Lukas , Frankish Adam , MacArthur Daniel G. , Harte Rachel , Tyler-Smith Chris , Harrow Jennifer , Gerstein Mark
Published: January 2011

The first wave of personal genomes documents how no single individual genome contains the full complement of functional genes. Here, we describe the extent of variation in gene and pseudogene numbers between individuals arising from inactivation events such as premature termination or aberrant splicing due to single-nucleotide polymorphisms. This highlights the inadequacy of the current reference sequence and gene set. We present a proposal to define a reference gene set that will remain stable as more individuals are sequenced. In particular, we recommend that the ancestral allele be used to define the reference sequence from which a core human reference gene annotation set can be derived. In addition, we call for the development of an expanded gene set to include human-specific genes that have arisen recently and are absent from the ancestral set.
Regulation of E2Fs and senescence by PML nuclear bodies
Authors: Vernier Mathieu , Bourdeau Véronique , Gaumont-Leclerc Marie-France , Moiseeva Olga , Bégin Virginie , Saad Fred , Mes-Masson Anne-Marie , Ferbeyre Gerardo
Published: January 2011

The tumor suppressor PML (promyelocytic leukemia protein) regulates cellular senescence and terminal differentiation, two processes that implicate a permanent exit from the cell cycle. Here, we show that the mechanism by which PML induces a permanent cell cycle exit and activates p53 and senescence involves a recruitment of E2F transcription factors bound to their promoters and the retinoblastoma (Rb) proteins to PML nuclear bodies enriched in heterochromatin proteins and protein phosphatase 1α. Blocking the functions of the Rb protein family or adding back E2Fs to PML-expressing cells can rescue their defects in E2F-dependent gene expression and cell proliferation, inhibiting the senescent phenotype. In benign prostatic hyperplasia, a neoplastic disease that displays features of senescence, PML was found to be up-regulated and forming nuclear bodies. In contrast, PML bodies were rarely visualized in prostate cancers. The newly defined PML/Rb/E2F pathway may help to distinguish benign tumors from cancers, and suggest E2F target genes as potential targets to induce senescence in human tumors.
Disruption of telomerase trafficking by TCAB1 mutation causes dyskeratosis congenita
Authors: Zhong Franklin , Savage Sharon A. , Shkreli Marina , Giri Neelam , Jessop Lea , Myers Timothy , Chen Renee , Alter Blanche P. , Artandi Steven E.
Published: January 2011

Dyskeratosis congenita (DC) is a genetic disorder of defective tissue maintenance and cancer predisposition caused by short telomeres and impaired stem cell function. Telomerase mutations are thought to precipitate DC by reducing either the catalytic activity or the overall levels of the telomerase complex. However, the underlying genetic mutations and the mechanisms of telomere shortening remain unknown for as many as 50% of DC patients, who lack mutations in genes controlling telomere homeostasis. Here, we show that disruption of telomerase trafficking accounts for unknown cases of DC. We identify DC patients with missense mutations in TCAB1, a telomerase holoenzyme protein that facilitates trafficking of telomerase to Cajal bodies. Compound heterozygous mutations in TCAB1 disrupt telomerase localization to Cajal bodies, resulting in misdirection of telomerase RNA to nucleoli, which prevents telomerase from elongating telomeres. Our findings establish telomerase mislocalization as a novel cause of DC, and suggest that telomerase trafficking defects may contribute more broadly to the pathogenesis of telomere-related disease.
Observation and prediction of recurrent human translocations mediated by NAHR between nonhomologous chromosomes
Authors: Ou Zhishuo , Stankiewicz Paweł , Xia Zhilian , Breman Amy M. , Dawson Brian , Wiszniewska Joanna , Szafranski Przemyslaw , Cooper M. Lance , Rao Mitchell , Shao Lina , South Sarah T. , Coleman Karlene , Fernhoff Paul M. , Deray Marcel J. , Rosengren Sally , Roeder Elizabeth R. , Enciso Victoria B. , Chinault A. Craig , Patel Ankita , Kang Sung-Hae L. , Shaw Chad A. , Lupski James R. , Cheung Sau W.
Published: January 2011

Four unrelated families with the same unbalanced translocation der(4)t(4;11)(p16.2;p15.4) were analyzed. Both of the breakpoint regions in 4p16.2 and 11p15.4 were narrowed to large ∼359-kb and ∼215-kb low-copy repeat (LCR) clusters, respectively, by aCGH and SNP array analyses. DNA sequencing enabled mapping the breakpoints of one translocation to 24 bp within interchromosomal paralogous LCRs of ∼130 kb in length and 94.7% DNA sequence identity located in olfactory receptor gene clusters, indicating nonallelic homologous recombination (NAHR) as the mechanism for translocation formation. To investigate the potential involvement of interchromosomal LCRs in recurrent chromosomal translocation formation, we performed computational genome-wide analyses and identified 1143 interchromosomal LCR substrate pairs, >5 kb in size and sharing >94% sequence identity that can potentially mediate chromosomal translocations. Additional evidence for interchromosomal NAHR mediated translocation formation was provided by sequencing the breakpoints of another recurrent translocation, der(8)t(8;12)(p23.1;p13.31). The NAHR sites were mapped within 55 bp in ∼7.8-kb paralogous subunits of 95.3% sequence identity located in the ∼579-kb (chr 8) and ∼287-kb (chr 12) LCR clusters. We demonstrate that NAHR mediates recurrent constitutional translocations t(4;11) and t(8;12) and potentially many other interchromosomal translocations throughout the human genome. Furthermore, we provide a computationally determined genome-wide “recurrent translocation map.”
Dot Blot Assay for Determining Fusion Protein Antiserum Quality
Authors: Rebay Ilaria , Fehon Richard G.
Published: January 2011

INTRODUCTION

When testing antiserum quality, it is essential to determine first whether the antiserum recognizes the fusion protein against which it was raised. A dot blot will provide a qualitative estimate of antibody titer, as described in this protocol. The same test can be done quantitatively by enzyme-linked immunosorbent assay (ELISA), but the technically simpler dot blot gives adequate information, uses less protein, and does not require an ELISA plate reader. If the same protein has been expressed in two different fusion-protein vectors, the test should be performed with the protein not used for immunization. If there is only one fusion protein—e.g., a glutathione-S-transferase (GST)-fusion—a second dot blot can be done in parallel with GST alone to compare the titers. If the antiserum recognizes the protein, there should be a lower titer of antibodies against GST alone as compared to the entire fusion protein. A preimmune control is always advisable. If a positive result is not obtained against the fusion protein, it is futile to proceed to secondary tests. Continue boosting and retesting until a positive response is achieved, or try a different approach.
Determining Fusion Protein Antiserum Quality by Staining of Transfected Drosophila S2 Cultured Cells
Authors: Rebay Ilaria , Fehon Richard G.
Published: January 2011

INTRODUCTION

Once antibodies against a Drosophila protein have been produced and an antiserum is determined to have a high titer against the fusion protein used for immunization, the next step is to ask whether the antiserum recognizes the appropriate antigen in Drosophila tissues. This protocol describes staining of transfected S2 cells for testing antisera. There are several advantages to using transfected S2 cells as a first tissue test. First, the antibody only needs to penetrate a single cell. In addition, these cells are easy to fix and stain and require no dissection. Second, the overexpressed protein will be easier to detect than lower levels of endogenous protein. Third, background is generally less of a problem in S2 cells than in embryonic or imaginal tissues, allowing lower dilutions of the antiserum to be tested if the response is marginal. Finally, the untransfected cells form a useful built-in control. S2 cell stainings are also an easy way to determine the subcellular localization of a particular protein.
Preparing Thick Sections of Frozen Adult Drosophila Retinas for Microscopy
Authors: Wolff Tanya
Published: January 2011

INTRODUCTION

This protocol is used for light microscopic analysis of the adult Drosophila eye. It provides nice preservation of pigment granules and photoreceptor rhabdomeres. Therefore, it is used primarily for phenotypic and mosaic analysis of adult eyes. Because this fixation method does not preserve either cell membranes or subcellular structures, transmission electron microscopy (TEM) is recommended for visualizing these structures.
Electroretinogram Recordings of Drosophila: FIGURE 1.
Authors: Dolph Patrick , Nair Amit , Raghu Padinjat
Published: January 2011

INTRODUCTION

Analysis of visual physiology in Drosophila photoreceptors has been central to understanding a number of important areas of modern biology, including the G-protein-coupled receptor cycle, phosphoinositide signaling, and calcium signaling. Analysis of photoreceptor performance and synaptic transmission are areas of neurobiology that have been studied using Drosophila photoreceptors as a model system. Electrophysiological analysis of responses to light is a powerful tool for characterizing and understanding visual transduction in Drosophila photoreceptors, and electroretinograms (ERGs) have long been used as a physiological assay in the Drosophila visual system. In these recordings, a microelectrode is placed on the eye and a reference electrode is placed elsewhere on the animal (typically in the thorax). Upon light stimulation, the voltage difference between these two electrodes is measured and displayed in real time. Because recordings are performed in live animals, all photoreceptor cells are intact and therefore surrounded by fluid containing endogenous concentrations of ions. Moreover, synaptic transmission between the photoreceptor and downstream laminar neurons can be detected.
Labeling Membranes with Carbocyanine Dyes (DiIs) as Phospholipid Analogs: FIGURE 1.
Authors: Chazotte Brad
Published: January 2011

INTRODUCTION

Cell membranes can be labeled with cationic lipophilic fluorescent carbocyanine dyes that function as phospholipid analogs. These dyes, such as DiI-C16(3) (1,1′-dihexadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate), label the plasma membrane and (eventually) label all of the membranes within a living cell. The dyes can be also used with model membranes. Carbocyanine dyes are commercially available in different carbon chain lengths (e.g., C12, C14, C18, and C22). Depending on the fatty acid composition of the phospholipids in the membrane studied with respect to chain length and degree of saturation, DiIs with different chain lengths can provide optimal incorporation and accurate reporting of membrane motions. DiI-labeled cells can be studied using fluorescence microscopy or fluorescence recovery after photobleaching (FRAP), as well as other techniques.
NanoCAGE: A High-Resolution Technique to Discover and Interrogate Cell Transcriptomes
Authors: Salimullah Md , Mizuho Sakai , Plessy Charles , Carninci Piero
Published: January 2011

INTRODUCTION

Cap analysis gene expression (CAGE) is a method to identify the 5′ ends of transcripts, allowing the discovery of new promoters and the quantification of gene activity. Combining promoter location and their expression levels, CAGE data are essential for annotation-agnostic studies of regulatory gene networks. However, CAGE requires large amounts of input RNA, which usually are not obtainable from highly refined samples such as tissue microdissections or subcellular fractions. The nanoCAGE method can capture the 5′ ends of transcripts from as little as 10 ng of total RNA and takes advantage of the capacity of current sequencers to produce longer (50-100 bp) reads. The method prepares cap-selected cDNAs ready for direct sequencing of their 5′ ends (optionally mate-paired with the 3′ end) that can provide information about downstream sequences. This protocol describes how to prepare nanoCAGE libraries from as little as 50 ng of total RNA within two working days. The libraries can be sequenced using an Illumina Gene AmplifierIIx with a level of sensitivity 1000 times higher than CAGE.
Multiple Testing and Power Calculations in Genetic Association Studies
Authors: So Hon-Cheong , Sham Pak C.
Published: January 2011

INTRODUCTION

Modern genetic association studies typically involve multiple single-nucleotide polymorphisms (SNPs) and/or multiple genes. With the development of high-throughput genotyping technologies and the reduction in genotyping cost, investigators can now assay up to a million SNPs for direct or indirect association with disease phenotypes. In addition, some studies involve multiple disease or related phenotypes and use multiple methods of statistical analysis. The combination of multiple genetic loci, multiple phenotypes, and multiple methods of evaluating associations between genotype and phenotype means that modern genetic studies often involve the testing of an enormous number of hypotheses. When multiple hypothesis tests are performed in a study, there is a risk of inflation of the type I error rate (i.e., the chance of falsely claiming an association when there is none). Several methods for multiple-testing correction are in popular use, and they all have strengths and weaknesses. Because no single method is universally adopted or always appropriate, it is important to understand the principles, strengths, and weaknesses of the methods so that they can be applied appropriately in practice. In this article, we review the three principle methods for multiple-testing correction and provide guidance for calculating statistical power.
Hypomorphic Alleles RevealFCA-Independent Roles forFYin the Regulation ofFLOWERING LOCUS C
Authors: Feng Wei , Jacob Yannick , Veley Kira M. , Ding Lei , Yu Xuhong , Choe Goh , Michaels Scott D.
Published: January 2011

The autonomous floral promotion pathway plays a key role in the regulation of flowering in rapid-cycling Arabidopsis (Arabidopsis thaliana) by providing constitutive repression of the floral inhibitor FLOWERING LOCUS C (FLC). As a result, autonomous pathway mutants contain elevated levels of FLC and are late flowering. Winter annual Arabidopsis, in contrast, contain functional alleles of FRIGIDA (FRI), which acts epistatically to the autonomous pathway to up-regulate FLC and delay flowering. To further explore the relationship between FRI and the autonomous pathway, we placed autonomous pathway mutants in a FRI-containing background. Unexpectedly, we found that a hypomorphic allele of the autonomous pathway gene fy (fy null alleles are embryo lethal) displayed background-specific effects on FLC expression and flowering time; in a rapid-cycling background fy mutants contained elevated levels of FLC and were late flowering, whereas in a winter annual background fy decreased FLC levels and partially suppressed the late-flowering phenotype conferred by FRI. Because FY has been shown to have homology to polyadenylation factors, we examined polyadenylation site selection in FLC transcripts. In wild type, two polyadenylation sites were detected and used at similar levels. In fy mutant backgrounds, however, the ratio of products was shifted to favor the distally polyadenylated form. FY has previously been shown to physically interact with another member of the autonomous pathway, FCA. Interestingly, we found that fy can partially suppress FLC expression in an fca null background and promote proximal polyadenylation site selection usage in the absence of FCA. Taken together, these results indicate novel and FCA-independent roles for FY in the regulation of FLC.
Activation of epidermal growth factor receptor signaling by the prostaglandin E2 receptor EP4 pathway during gastric tumorigenesis
Authors: Oshima Hiroko , Popivanova Boryana K. , Oguma Keisuke , Kong Dan , Ishikawa Tomo‐o , Oshima Masanobu
Published: January 2011

Cyclooxygenase‐2 (COX‐2) plays an important role in tumorigenesis through prostaglandin E2 (PGE2) biosynthesis. It has been shown by in vitro studies that PGE2 signaling transactivates epidermal growth factor receptor (EGFR) through an intracellular mechanism. However, the mechanisms underlying PGE2‐induced EGFR activation in in vivo tumors are still not fully understood. We previously constructed transgenic mice that develop gastric tumors caused by oncogenic activation and PGE2 pathway induction. Importantly, expression of EGFR ligands, epiregulin, amphiregulin, heparin‐binding EGF‐like growth factor, and betacellulin, as well as a disintegrin and metalloproteinases (ADAMs), ADAM8, ADAM9, ADAM10, and ADAM17 were significantly increased in the mouse gastric tumors in a PGE2 pathway‐dependent manner. These ADAMs can activate EGFR by ectodomain shedding of EGFR ligands. Notably, the extensive induction of EGFR ligands and ADAMs was suppressed by inhibition of the PGE2 receptor EP4. Moreover, EP4 signaling induced expression of amphiregulin and epiregulin in activated macrophages, whereas EP4 pathway was required for basal expression of epiregulin in gastric epithelial cells. In contrast, ADAMs were not induced directly by PGE2 in these cells, suggesting indirect mechanism possibly through PGE2‐associated inflammatory responses. These results suggest that PGE2 signaling through EP4 activates EGFR in gastric tumors through global induction of EGFR ligands and ADAMs in several cell types either by direct or indirect mechanism. Importantly, gastric tumorigenesis of the transgenic mice was significantly suppressed by combination treatment with EGFR and COX‐2 inhibitors. Therefore, it is possible that inhibition of both COX‐2/PGE2 and EGFR pathways represents an effective strategy for preventing gastric cancer. (Cancer Sci 2011; 102: 713–719)
Inactivation of Snt2, a BAH/PHD‐containing transcription factor, impairs pathogenicity and increases autophagosome abundance in Fusarium oxysporum
Authors: DENISOV YOULIA , FREEMAN STANLEY , YARDEN ODED
Published: January 2011

The soil‐borne, asexual fungus Fusarium oxysporum f.sp. melonis (FOM) is a causal agent of muskmelon wilt disease. The current study focused on the most virulent race of FOM—race 1,2. The tagged mutant D122, generated by Agrobacterium tumefaciens‐mediated transformation, caused the delayed appearance of initial wilt disease symptoms, as well as a 75% reduction in pathogenicity. D122 was impaired in the gene product homologous to the Snt2‐like transcription factor of Schizosaccharomyces pombe. Involvement of snt2 in the early stage of FOM pathogenesis and its requirement for host colonization were confirmed by targeted disruption followed by quantitative reverse transcription‐polymerase chain reaction analysis of snt2 expression in planta. Δsnt2 mutants of FOM and Neurospora crassa exhibited similar morphological abnormalities, including a reduction in conidia production and biomass accumulation, slower vegetative growth and frequent hyphal septation. In N. crassa, snt‐2 is required for sexual development, as Δsnt‐2 mutants were unable to produce mature perithecia. Suppressive subtraction hybridization analysis of the D122 mutant versus wild‐type isolate detected four genes (idi4, pdc, msf1, eEF1G) that were found previously in association with the target of rapamycin (TOR) kinase pathway. Expression of the autophagy‐related idi4 and pdc genes was found to be up‐regulated in the Δsnt2 FOM mutant. In N. crassa, disruption of snt‐2 also conferred a significant over‐expression of idi4.
The structure of the Helicobacter pylori ferric uptake regulator Fur reveals three functional metal binding sites
Authors: Dian Cyril , Vitale Sylvia , Leonard Gordon A. , Bahlawane Christelle , Fauquant Caroline , Leduc Damien , Muller Cécile , de Reuse Hilde , Michaud‐Soret Isabelle , Terradot Laurent
Published: January 2011

Fur, the ferric uptake regulator, is a transcription factor that controls iron metabolism in bacteria. Binding of ferrous iron to Fur triggers a conformational change that activates the protein for binding to specific DNA sequences named Fur boxes. In Helicobacter pylori, HpFur is involved in acid response and is important for gastric colonization in model animals. Here we present the crystal structure of a functionally active HpFur mutant (HpFur2M; C78S‐C150S) bound to zinc. Although its fold is similar to that of other Fur and Fur‐like proteins, the crystal structure of HpFur reveals a unique structured N‐terminal extension and an unusual C‐terminal helix. The structure also shows three metal binding sites: S1 the structural ZnS4 site previously characterized biochemically in HpFur and the two zinc sites identified in other Fur proteins. Site‐directed mutagenesis and spectroscopy analyses of purified wild‐type HpFur and various mutants show that the two metal binding sites common to other Fur proteins can be also metallated by cobalt. DNA protection and circular dichroism experiments demonstrate that, while these two sites influence the affinity of HpFur for DNA, only one is absolutely required for DNA binding and could be responsible for the conformational changes of Fur upon metal binding while the other is a secondary site.
Integration of sedimentology and ground‐penetrating radar for high‐resolution imaging of a carbonate platform
Authors: JORRY STÉPHAN J. , BIÉVRE GRÉGORY
Published: January 2011

Ground‐penetrating radar has not been applied widely to the recognition of ancient carbonate platform geometries. This article reports the results of an integrated study performed on an Upper Jurassic outcrop from the south‐east Paris basin, where coral bioherms laterally change into prograding depositional sequences. Ground‐penetrating radar profiles illustrate the different bedding planes and major erosional unconformities visible at outcrop. A ground‐penetrating radar profile conducted at the base of the cliff displays a palaeotopographic surface on which the outcropping bioherms settled. The excellent penetration depths of the ground‐penetrating radar (20 m with a monostatic 200 MHz antenna) images the carbonate platform geometries, ranging between outcrop workscale (a few metres) and seismic scale (several hundreds of metres). This study supports recent evidence of icehouse conditions and induced sea‐level fluctuations controlling the Upper Jurassic carbonate production.
On the head morphology of Grylloblattodea (Insecta) and the systematic position of the order, with a new nomenclature for the head muscles of Dicondylia
Authors: WIPFLER BENJAMIN , MACHIDA RYUICHIRO , MÜLLER BERND , BEUTEL ROLF G.
Published: January 2011

External and internal head structures of adults of Galloisiana yuasai (Grylloblattodea) are described. The results are compared with conditions found in representatives of other lower neopteran lineages, notably in Austrophasma and Karoophasma (both Mantophasmatodea). Sutures and ridges of the head capsule are discussed. A new nomenclature for head muscles is presented for the entire Dicondylia (= Zygentoma + Pterygota). Galloisiana (like its sister taxon Grylloblatta) is mostly characterized by plesiomorphic features, such as the largely unspecialized orthopteroid mouthparts, the multisegmented filiform antennae, the presence of trabeculae tentorii, the absence of muscles associated with the antennal ampullae, the presence of musculus stipitalis transversalis (0mx11) and the presence of musculus tentoriofrontalis anterior (0te2). Autapomorphies of Grylloblattodea are: (i) compound eyes composed of only 60 ommatidia or less; (ii) a lacinia with a proximal tooth; (iii) a rounded submentum; (iv) loss of musculus craniohypopharyngealis (0hy3); and (v) loss of musculus labroepipharyngealis (0lb5). The phylogenetic evaluation of 104 characters of the head yields a branching pattern with Grylloblattodea as a sister group of Mantophasmatodea in clade Xenonomia. Putative synapomorphies of both taxa are: (i) a distinct angle (more than 60°) between the submentum and the mentum; (ii) posteriorly oriented labial palpi; (iii) a flat and lobe‐like hypopharynx with a suspensorium far ventrad of the anatomical mouth opening; (iv) loss of musculus tentorioparaglossalis (0la6); and (v) a connection between the antennal ampulla and the supraoesophageal ganglion containing nuclei. Xenonomia is placed in a clade with the two dictyopteran terminals. Another monophyletic group is Embioptera + Phasmatodea. Most branches of the single tree obtained in our analysis are weakly supported. The results clearly show that more data and a much broader taxon sampling are required to clarify the phylogenetic interrelationships of the lower neopteran orders. However, our results narrow down the spectrum of possible solutions, and represent a starting point for future phylogenetic analyses, with an extensive concatenated dataset.
Presynaptic facilitatory adenosine A2A receptors mediate fade induced by neuromuscular relaxants that exhibit anticholinesterase activity
Authors: Bornia Elaine CS , Correia‐de‐Sá Paulo , Alves‐Do‐Prado Wilson
Published: January 2011

1. Pancuronium, cisatracurium and vecuronium are antinicotinic agents that, in contrast with d‐tubocurarine and hexamethonium, exhibit anticholinesterase activity. Pancuronium‐, cisatracurium‐ and vecuronium‐induced fade results from blockade of facilitatory nicotinic receptors on motor nerves, but fade produced by such agents also depends on the presynaptic activation of inhibitory muscarinic M2 receptors by acetylcholine released from motor nerve terminals and activation of inhibitory adenosine A1 receptors by adenosine released from motor nerves and muscles. The participation of presynaptic facilitatory A2A receptors in fade caused by pancuronium, cisatracurium and vecuronium has not yet been investigated. In the present study, we determined the effects of ZM 241385, an antagonist of presynaptic facilitatory A2A receptors, on fade produced by these neuromuscular relaxants in the rat phrenic nerve–diaphragm (PND) preparation.

2. The muscles were stimulated indirectly at 75 ± 3 Hz to induce a sustained tetanizing muscular contraction. The lowest concentration at which each antinicotinic agent produced fade without modifying initial tetanic tension (presynaptic action) was determined.

3. d‐Tubocurarine‐induced fade occurred only at 55 nmol/L, a concentration that also reduced maximal tetanic tension (post‐synaptic action). At 10 nmol/L, ZM 241385 alone did not produce fade, but it did attenuate pancuronium (0.32 μmol/L)‐, cisatracurium (0.32 μmol/L)‐ and vecuronium (0.36 μmol/L)‐induced fade.

4. The fade induced by the ‘pure’ antinicotinic agents d‐tubocurarine (55 nmol/L) and hexamethonium (413 μmol/L) was not altered by 10 nmol/L ZM 241385, indicating that presynaptic adenosine A2A receptors play a significant role in the fade produced by antinicotinic agents when such agents have anticholinesterase activity.
Clinicopathological staging of colorectal cancer: Evolution and consensus—an Australian perspective
Authors: Chapuis Pierre H , Chan Charles , Dent Owen F
Published: January 2011

In 1991 this journal published the report of an international working party to the World Congress of Gastroenterology regarding the clinicopathological staging of colorectal cancer. Since that time staging has continued to evolve as further prognostic factors in colorectal cancer have been elucidated in studies of increasingly large databases in several countries. This review summarizes several of the key issues that have arisen during this evolutionary process and raises matters which still remain controversial in staging at the present time.
Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis in Japan
Authors: Okanoue Takeshi , Umemura Atsushi , Yasui Kohichiroh , Itoh Yoshito
Published: January 2011

During the past 20 to 30 years, the frequency of patients presenting with nonalcoholic fatty liver diseases (NAFLD) has increased gradually in Japan in proportion to the increase in the population with life‐style related diseases. We describe here the current status of the clinical and basic aspects of research into NAFLD in Japan.

The increase in the incidence of life‐style‐related diseases has resulted in an increase in NAFLD throughout the past 20 to 30 years. The rate of obesity in the population is not high compared to western countries but the incidence of NAFLD is similar to those countries. In 2008 we started a nationwide study of NAFLD which has been supported by the Ministry of Labor and Welfare Japan. In this project, we planned to investigate the epidemiology, genetic backgrounds and biochemical markers, and liver injury in patients with diabetes mellitus (DM) and hepatocellular carcinoma in NASH, and treatment of NASH. Approximately 20 to 25% of DM patients showed NAFLD in which the prevalence of NASH might be more than 30 to 40%. Fortunately, we have been able to obtain very interesting results from our group studies, including single necleotide polymorphisms (SNPs) which will be published in the near future.
Changing etiologies and outcomes of acute liver failure: A perspective from Japan
Authors: Oketani Makoto , Ido Akio , Tsubouchi Hirohito
Published: January 2011

Acute liver failure in Japan usually consists of fulminant hepatitis (FH) due to viral infection, autoimmune hepatitis and drug‐allergy‐induced liver injury. The annual incidence of FH was estimated at 429 cases in 2004. FH is classified into acute or subacute type, and the prognosis of the latter is poor. Hepatitis B virus (HBV) is the most frequently identifiable agent that causes FH in Japan. Transient HBV infection is more prevalent in the acute than subacute type, whereas the frequency of HBV carriers is greater in the subacute type. FH due to HBV reactivation from resolved hepatitis B has been increasingly observed in patients with malignant lymphoma treated with rituximab and corticosteroid combination therapy. The prognosis is poor in HBV carriers with acute exacerbation, especially in patients with HBV reactivation from resolved hepatitis B. Despite careful investigation, the etiology is still unknown in 16% and 39% of the acute and subacute type of FH, respectively. Autoimmune hepatitis and drug‐allergy‐induced liver injury are found in 7% and 10%, respectively, and are more frequently observed in the subacute type of FH. Living donor liver transplantation is now the standard care for individuals with poor prognosis. Artificial liver support with plasmapheresis and hemodiafiltration plays a central role while waiting for a donor liver or for the native liver to regenerate. Further research is necessary to identify the causes of unknown origin. In addition, to improve the prognosis of FH, it is necessary to establish treatment modalities that are effective for liver regeneration.
Terlipressin in hepatorenal syndrome: Evidence for present indications
Authors: Rajekar Harshal , Chawla Yogesh
Published: January 2011

Hepatorenal syndrome (HRS) is the most frequent life threatening complication of advanced liver failure and cirrhosis. HRS results from a functional renal dysfunction due to circulatory disturbances in patients with advanced liver disease and portal hypertension. Reduction in the effective circulating blood volume and hence hypoperfusion of the kidney is the basic underlying common pathogenetic mechanism for the development of hepatorenal syndrome. The prognosis for HRS remains very poor with types 1 and 2—both having an expected survival time of 2 weeks and 6 months, respectively.

Although the available data are derived from studies including a limited number of patients mainly affected by type 1 HRS, vasoconstrictor drugs, in particular the vasopressin analog Terlipressin, seem to be the most effective approach for the management of HRS. Associated with albumin infusion, these drugs have been shown to lead to reduced mortality and improved renal function in HRS. Terlipressin administration significantly increases mean arterial pressure and systemic vascular resistance; while the heart rate, cardiac output, HVPG and portal venous blood flow decrease significantly. This decrease correlates well with the decrease in plasma renin activity. Thus the vasoconstrictor effect of Terlipressin reverses the basic pathology of HRS by reducing the plasma renin activity. The improvement in hemodynamics with Terlipressin is associated with an increase in glomerular filtration rate and deactivation of the vasoconstrictor and sodium‐conserving hormones with reduced activity of the RAAS resulting in increased natriuresis.

Terlipressin thus reverses HRS and is useful in bridging the patient to liver transplantation and may hence indirectly improve survival. Patients with HRS who show an improvement in renal function with Terlipressin and albumin seem to have an excellent post‐transplantation outcome similar to that of patients without HRS. Thus, the use of Terlipressin has been shown to be safe, with minimal side effects that usually disappear after dose reduction, and results in an improved outcome in patients with HRS.