bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of GSK2334470, a novel and highly specific inhibitor of PDK1
Authors: Najafov Ayaz , Sommer Eeva M. , Axten Jeffrey M. , Deyoung M. Phillip , Alessi Dario R. 
Published: November 2010

PDK1 (3-phosphoinositide-dependent protein kinase 1) activates a group of protein kinases belonging to the AGC [PKA (protein kinase A)/PKG (protein kinase G)/PKC (protein kinase C)]-kinase family that play important roles in mediating diverse biological processes. Many cancer-driving mutations induce activation of PDK1 targets including Akt, S6K (p70 ribosomal S6 kinase) and SGK (serum- and glucocorticoid-induced protein kinase). In the present paper, we describe the small molecule GSK2334470, which inhibits PDK1 with an IC50 of ~10 nM, but does not suppress the activity of 93 other protein kinases including 13 AGC-kinases most related to PDK1 at 500-fold higher concentrations. Addition of GSK2334470 to HEK (human embryonic kidney)-293, U87 or MEF (mouse embryonic fibroblast) cells ablated T-loop residue phosphorylation and activation of SGK isoforms and S6K1 induced by serum or IGF1 (insulin-like growth factor 1). GSK2334470 also inhibited T-loop phosphorylation and activation of Akt, but was more efficient at inhibiting Akt in response to stimuli such as serum that activated the PI3K (phosphoinositide 3-kinase) pathway weakly. GSK2334470 inhibited activation of an Akt1 mutant lacking the PH domain (pleckstrin homology domain) more potently than full-length Akt1, suggesting that GSK2334470 is more effective at inhibiting PDK1 substrates that are activated in the cytosol rather than at the plasma membrane. Consistent with this, GSK2334470 inhibited Akt activation in knock-in embryonic stem cells expressing a mutant of PDK1 that is unable to interact with phosphoinositides more potently than in wild-type cells. GSK2334470 also suppressed T-loop phosphorylation and activation of RSK2 (p90 ribosomal S6 kinase 2), another PDK1 target activated by the ERK (extracellular-signal-regulated kinase) pathway. However, prolonged treatment of cells with inhibitor was required to observe inhibition of RSK2, indicating that PDK1 substrates possess distinct T-loop dephosphorylation kinetics. Our data define how PDK1 inhibitors affect AGC signalling pathways and suggest that GSK2334470 will be a useful tool for delineating the roles of PDK1 in biological processes.
Angiotensin-(1–7) infusion is associated with increased blood pressure and adverse cardiac remodelling in rats with subtotal nephrectomy
Authors: Velkoska Elena , Dean Rachael G. , Griggs Karen , Burchill Luke , Burrell Louise M. 
Published: November 2010

ACE (angiotensin-converting enzyme) 2 is expressed in the heart and kidney and metabolizes Ang (angiotensin) II to Ang-(1–7) a peptide that acts via the Ang-(1–7) or mas receptor. The aim of the present study was to assess the effect of Ang-(1–7) on blood pressure and cardiac remodelling in a rat model of renal mass ablation. Male SD (Sprague–Dawley) rats underwent STNx (subtotal nephrectomy) and were treated for 10 days with vehicle, the ACE inhibitor ramipril (oral 1 mg·kg−1 of body weight·day−1) or Ang-(1–7) (subcutaneous 24 μg·kg−1 of body weight·h−1) (all n = 15 per group). A control group (n = 10) of sham-operated rats were also studied. STNx rats were hypertensive (P&lt;0.01) with renal impairment (P&lt;0.001), cardiac hypertrophy (P&lt;0.001) and fibrosis (P&lt;0.05), and increased cardiac ACE (P&lt;0.001) and ACE2 activity (P&lt;0.05). Ramipril reduced blood pressure (P&lt;0.01), improved cardiac hypertrophy (P&lt;0.001) and inhibited cardiac ACE (P&lt;0.001). By contrast, Ang-(1–7) infusion in STNx was associated with further increases in blood pressure (P&lt;0.05), cardiac hypertrophy (P&lt;0.05) and fibrosis (P&lt;0.01). Ang-(1–7) infusion also increased cardiac ACE activity (P&lt;0.001) and reduced cardiac ACE2 activity (P&lt;0.05) compared with STNx-vehicle rats. Our results add to the increasing evidence that Ang-(1–7) may have deleterious cardiovascular effects in kidney failure and highlight the need for further in vivo studies of the ACE2/Ang-(1–7)/mas receptor axis in kidney disease.
Differences and similarities between chronic obstructive pulmonary disease and asthma
Authors: Jeffery P. K. 
Published: November 2010

Asthma and chronic obstructive pulmonary disease (COPD) are complex conditions with imprecise definitions, which make definitive morphological comparisons difficult. The airways in asthma are occluded by tenacious plugs of exudate and mucus, and there is fragility of airway surface epithelium, thickening of the reticular layer beneath the epithelial basal lamina (the last two not usually features of COPD), and bronchial vessel congestion and oedema. There is an increased inflammatory infiltrate comprising ‘activated’ lymphocytes and eosinophils with release of granular content in the latter, and enlargement of bronchial smooth muscle, particularly in medium‐sized bronchi. CD4+ve lymphocytes predominate over CD8+ve cells and neutrophils are sparse.In contrast, three conditions contribute to COPD. In chronic bronchitis there is cough and mucous hypersecretion with enlargement of tracheobronchial submucosal glands and a disproportionate increase of mucous acini. CD8+ve lymphocytes predominate over CD4+ve cells and there are increased numbers of subepithelial macrophages and intra‐epithelial neutrophils. Exacerbations of bronchitis are associated with a tissue eosinophilia, apparent absence of IL‐5 protein but gene expression for IL‐4 and IL‐5 is present. In small or peripheral airways disease, there is inflammation of bronchioli and mucous metaplasia and hyperplasia, with increased intraluminal mucus, increased wall muscle, fibrosis, and airway stenoses (also referred to as chronic obstructive bronchiolitis). Respiratory bronchiolitis involving increased numbers of pigmented macrophages is a critically important early lesion. Increasingly severe peribronchiolitis includes infiltration of T lymphocytes in which the CD8+ subset again predominates. These inflammatory changes may predispose to the development of centrilobular emphysema and reduced FEV1 via the destruction of alveolar attachments. In emphysema there is abnormal, permanent enlargement of airspaces distal to the terminal bronchiolus (i.e. within the acinus) accompanied by destruction of alveolar walls and without obvious fibrosis. The severity of emphysema, rather than type, appears to be the most important determinant of chronic deterioration of airflow, and in this there may be significant loss of elastic recoil and microscopic emphysema prior to the observed macroscopic destruction of the acinus.
Clinical practice evaluation of atosiban in preterm labour management in six European countries
Authors: Husslein P , Roura LC , Dudenhausen J , Helmer H , Frydman R , Rizzo N , Schneider D ,   TREASURE study group
Published: November 2010

Objective  To evaluate the efficacy and safety of early administration compared with standard administration of atosiban, when predefined eligibility criteria were met.Design  A prospective, open‐label, randomised clinical trial. Women were randomised to receive atosiban either immediately (early) or when specified criteria, in terms of duration/frequency of uterine contraction or status of cervical dilation/effacement, were fulfilled (standard).Setting  Carried out at 105 centres in six European countries.Population  Pregnant women admitted to hospital in threatened preterm labour between 24 and 34 weeks of gestation, comprising a subgroup of women enrolled in the Tractocile Efficacy Assessment Survey in Europe (TREASURE) clinical experience review.Main outcome measures  Efficacy was defined as the successful delay of delivery with no alternative tocolytic agent for 48 hours.Results  More women in the early group remained undelivered at 48 hours with no alternative tocolytic agent compared with those who received atosiban when specified criteria were fulfilled (88.9 versus 76.1%; P = 0.03). Safety was comparable between the groups. There were no statistical differences in maternal, fetal or neonatal adverse events between the early and standard atosiban arms.Conclusions  The use of atosiban was effective for the delay of preterm labour and presented no safety concerns irrespective of the time it was administered.
Intrapartum ultrasound estimation of total bladder volume
Authors: Gyampoh B. , Crouch N. , O'Brien P. , O'Sullivan C. , Cutner A. 
Published: November 2010

Objective  To determine whether real‐time ultrasound measurement of multiple linear dimensions of the bladder could be used to estimate total bladder volumes of women in labour.Aim  To create a simple reproducible formula using ultrasound techniques to help estimate total bladder volumes of women in labour. This may prevent unnecessary catheterisation and conversely, avoid failure to catheterise when indicated, thereby reducing the complications associated with catheterisation and bladder overdistension.Design  Prospective, observational study of women in labour.Setting  Delivery Suite, Obstetric Hospital, University College London Hospitals.Population  Forty‐nine women in labour recommended for catheterisation by their attending midwives.Method  A real‐time ultrasound scanner was used to measure bladder diameters in two planes: transverse width and height, and sagittal width and height. A Foley's catheter was inserted and the bladder drained into a graduated bowl under sterile conditions. These values and urine volumes were recorded and a formula for detecting bladder volumes above 300 mL was developed using linear regression methods and the Bland–Altman limits of agreement.Main outcome measure  Sensitivity and specificity of derived formulae in predicting bladder volume from ultrasound measurements. Correctly predicted volumes greater than 300 mL.Results  Among the 49 women, 36 were nulliparous and 13 were multiparous. All had full‐term pregnancies with cephalic presentation and were in active labour with cervical dilatations ranging from 3 to 10 cm. There were no previous caesarean sections among the multiparous women. Thirty‐nine women had epidural analgesia. Indications for catheterisation included a palpable bladder per abdomen, or the interval from last urine voided. The catheterised volumes ranged from 30 to 720 mL with a median of 150 mL. The new equation (0.68 ×h×d×w) had a sensitivity of 77% (95% CI 46–95%) and specificity of 86% (95% CI 71–95%) for detecting bladder volumes greater than 300 mL. In order to ensure that about 95% of women in need of catheterisation are detected, the above equation was improved using the Bland–Altman limits of agreement. The sensitivity of this final equation (1.74 ×h×d×w) was 100% (95% CI 75–100%) and the specificity dropped to 36% (95% CI 21–54%).Conclusion  It is possible to use real‐time ultrasound in estimation of total bladder volumes of women in labour. The implications are that all of those normally selected as being in need of catheterisation could be detected, while about a quarter of those women would avoid unnecessary catheterisation.
GPU-BLAST: using graphics processors to accelerate protein sequence alignment
Authors: Vouzis Panagiotis D. , Sahinidis Nikolaos V. 
Published: November 2010

Abstract
Motivation: The Basic Local Alignment Search Tool (BLAST) is one of the most widely used bioinformatics tools. The widespread impact of BLAST is reflected in over 53 000 citations that this software has received in the past two decades, and the use of the word ‘blast’ as a verb referring to biological sequence comparison. Any improvement in the execution speed of BLAST would be of great importance in the practice of bioinformatics, and facilitate coping with ever increasing sizes of biomolecular databases.
Results: Using a general-purpose graphics processing unit (GPU), we have developed GPU-BLAST, an accelerated version of the popular NCBI-BLAST. The implementation is based on the source code of NCBI-BLAST, thus maintaining the same input and output interface while producing identical results. In comparison to the sequential NCBI-BLAST, the speedups achieved by GPU-BLAST range mostly between 3 and 4.
Availability: The source code of GPU-BLAST is freely available at http://archimedes.cheme.cmu.edu/biosoftware.html.
Contact: sahinidis@cmu.edu
Supplementary information: Supplementary data are available at Bioinformatics online.
Anatomy of a hash-based long read sequence mapping algorithm for next generation DNA sequencing
Authors: Misra Sanchit , Agrawal Ankit , Liao Wei-keng , Choudhary Alok 
Published: November 2010

Abstract
Motivation: Recently, a number of programs have been proposed for mapping short reads to a reference genome. Many of them are heavily optimized for short-read mapping and hence are very efficient for shorter queries, but that makes them inefficient or not applicable for reads longer than 200 bp. However, many sequencers are already generating longer reads and more are expected to follow. For long read sequence mapping, there are limited options; BLAT, SSAHA2, FANGS and BWA-SW are among the popular ones. However, resequencing and personalized medicine need much faster software to map these long sequencing reads to a reference genome to identify SNPs or rare transcripts.
Results: We present AGILE (AliGnIng Long rEads), a hash table based high-throughput sequence mapping algorithm for longer 454 reads that uses diagonal multiple seed-match criteria, customized q-gram filtering and a dynamic incremental search approach among other heuristics to optimize every step of the mapping process. In our experiments, we observe that AGILE is more accurate than BLAT, and comparable to BWA-SW and SSAHA2. For practical error rates (&lt; 5%) and read lengths (200–1000 bp), AGILE is significantly faster than BLAT, SSAHA2 and BWA-SW. Even for the other cases, AGILE is comparable to BWA-SW and several times faster than BLAT and SSAHA2.
Availability: http://www.ece.northwestern.edu/~smi539/agile.html.
Contact: smi539@eecs.northwestern.edu
Supplementary information: Supplementary data are available at Bioinformatics online.
Genetic Dissection of Barley Morphology and Development
Authors: Druka Arnis , Franckowiak Jerome , Lundqvist Udda , Bonar Nicola , Alexander Jill , Houston Kelly , Radovic Slobodanka , Shahinnia Fahimeh , Vendramin Vera , Morgante Michele , Stein Nils , Waugh Robbie 
Published: November 2010

AbstractSince the early 20th century, barley (Hordeum vulgare) has been a model for investigating the effects of physical and chemical mutagens and for exploring the potential of mutation breeding in crop improvement. As a consequence, extensive and well-characterized collections of morphological and developmental mutants have been assembled that represent a valuable resource for exploring a wide range of complex and fundamental biological processes. We constructed a collection of 881 backcrossed lines containing mutant alleles that induce a majority of the morphological and developmental variation described in this species. After genotyping these lines with up to 3,072 single nucleotide polymorphisms, comparison to their recurrent parent defined the genetic location of 426 mutant alleles to chromosomal segments, each representing on average &lt;3% of the barley genetic map. We show how the gene content in these segments can be predicted through conservation of synteny with model cereal genomes, providing a route to rapid gene identification.
Mycosphaerella fijiensis, the black leaf streak pathogen of banana: progress towards understanding pathogen biology and detection, disease development, and the challenges of control
Authors: CHURCHILL ALICE C. L. 
Published: November 2010

SUMMARYBackground: Banana (Musa spp.) is grown throughout the tropical and subtropical regions of the world. The fruits are a key staple food in many developing countries and a source of income for subsistence farmers. Bananas are also a major, multibillion‐dollar export commodity for consumption primarily in developed countries, where few banana cultivars are grown. The fungal pathogen Mycosphaerella fijiensis causes black leaf streak disease (BLSD; aka black Sigatoka leaf spot) on the majority of edible banana cultivars grown worldwide. The fact that most of these cultivars are sterile and unsuitable for the breeding of resistant lines necessitates the extensive use of fungicides as the primary means of disease control. BLSD is a significant threat to the food security of resource‐poor populations who cannot afford fungicides, and increases the environmental and health hazards where large‐acreage monocultures of banana (Cavendish subgroup, AAA genome) are grown for export.Taxonomy: Mycosphaerella fijiensis M. Morelet is a sexual, heterothallic fungus having Pseudocercospora fijiensis (M. Morelet) Deighton as the anamorph stage. It is a haploid, hemibiotrophic ascomycete within the class Dothideomycetes, order Capnodiales and family Mycosphaerellaceae. Its taxonomic placement is based on DNA phylogeny, morphological analyses and cultural characteristics.Disease symptoms and host range: Mycosphaerella fijiensis is a leaf pathogen that causes reddish‐brown streaks running parallel to the leaf veins, which aggregate to form larger, dark‐brown to black compound streaks. These streaks eventually form fusiform or elliptical lesions that coalesce, form a water‐soaked border with a yellow halo and, eventually, merge to cause extensive leaf necrosis. The disease does not kill the plants immediately, but weakens them by decreasing the photosynthetic capacity of leaves, causing a reduction in the quantity and quality of fruit, and inducing the premature ripening of fruit harvested from infected plants. Although Musa spp. are the primary hosts of M. fijiensis, the ornamental plant Heliconia psittacorum has been reported as an alternative host.New opportunities: Several valuable tools and resources have been developed to overcome some of the challenges of studying this host–pathogen system. These include a DNA‐mediated fungal transformation system and the ability to conduct targeted gene disruptions, reliable quantitative plant bioassays, diagnostic probes to detect and differentiate M. fijiensis from related pathogens and to distinguish strains of different mating types, and a genome sequence that has revealed a wealth of gene sequences and molecular markers to be utilized in functional and population biology studies.Useful websites: http://bananas.bioversityinternational.org/, http://genome.jgi‐psf.org/Mycfi2/Mycfi2.home.html, http://www.isppweb.org/names_banana_pathogen.asp#fun, http://www.promusa.org/
The beneficial effect of Trichoderma spp. on tomato is modulated by the plant genotype
Authors: TUCCI MARINA , RUOCCO MICHELINA , DE MASI LUIGI , DE PALMA MONICA , LORITO MATTEO 
Published: November 2010

SUMMARYRhizosphere‐competent fungi of the genus Trichoderma are widely used as biofertilizers and biopesticides in commercial formulates because of the multiple beneficial effects on plant growth and disease resistance. In this work, we demonstrate that genetic variability among wild and cultivated tomato lines affects the outcome of the interaction with two ‘elite’ biocontrol strains of T. atroviride and T. harzianum. The beneficial response, which included enhanced growth and systemic resistance against Botrytis cinerea, was clearly evident for some, but not all, the tested lines. At least in one case (line M82), treatment with the biocontrol agents had no effect or was even detrimental. Expression studies on defence‐related genes suggested that the fungus is able to trigger, in the responsive lines, a long‐lasting up‐regulation of the salicylic acid pathway in the absence of a pathogen, possibly activating a priming mechanism in the plant. Consequently, infection with B. cinerea on plants pretreated with Trichoderma is followed by enhanced activation of jasmonate‐responsive genes, eventually boosting systemic resistance to the pathogen in a plant genotype‐dependent manner. Our data indicate that, at least in tomato, the Trichoderma induced systemic resistance mechanism is much more complex than considered so far, and the ability of the plant to benefit from this symbiotic‐like interaction can be genetically improved.
The potent calcitonin gene‐related peptide receptor antagonist, telcagepant, does not affect nitroglycerin‐induced vasodilation in healthy men
Authors: Van der Schueren Bart J. , Blanchard Rebecca , Murphy M. Gail , Palcza John , De Lepeleire Inge , Van Hecken Anne , Depré Marleen , de Hoon Jan N. 
Published: November 2010

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Telcagepant (MK‐0974, Merck & Co., Inc.), an oral calcitonin gene‐related peptide (CGRP) antagonist, is effective in treating acute migraine headache. Although CGRP receptor antagonists seem devoid of direct vasoconstrictor activity, animal research suggests a role for CGRP in nitroglycerin (NTG) induced vasodilation. Pulse wave analysis and high resolution ultrasound are sensitive techniques to investigate cardiovascular responses to drugs in vivo in humans.WHAT THIS STUDY ADDS• This study shows that telcagepant, at a supra‐therapeutic dose for the treatment of acute migraine headache, has no clinically relevant effect on NTG‐induced haemodynamic changes in healthy male volunteers. There is also no measurable vasoconstrictor effect of telcagepant as such in both the central and peripheral vascular bed. The results of the present study support the favourable cardiovascular safety profile of telcagepant and indicate that CGRP is not involved in NTG‐induced vasodilation in humans.AIMS To assess the effect of the calcitonin gene‐related peptide (CGRP) receptor antagonist, telcagepant, on the haemodynamic response to sublingual nitroglycerin (NTG).METHODS Twenty‐two healthy male volunteers participated in a randomized, placebo‐controlled, double‐blind, two‐period, crossover study. Subjects received 500 mg telcagepant or placebo followed, 1.5 h later, by 0.4 mg NTG. To assess the haemodynamic response the following vascular parameters were measured: blood pressure, aortic augmentation index (AIx) and brachial artery diameter (BAD). Data are presented as mean (95% confidence interval, CI).RESULTS The aortic AIx following NTG decreased by −18.50 (−21.02, −15.98) % after telcagepant vs. −17.28 (−19.80, −14.76) % after placebo. The BAD fold increase following NTG was 1.14 (1.12, 1.17) after telcagepant vs. 1.13 (1.10, 1.15) after placebo. For both AIx and BAD, the hypothesis that telcagepant does not significantly affect the changes induced by NTG is supported (P < 0.0001). In addition, no vasoconstrictor effect of telcagepant could be demonstrated.CONCLUSIONS Telcagepant did not affect NTG‐induced haemodynamic changes. These data suggest that NTG‐induced vasodilation is not CGRP dependent.