bluuebunny/crossref_metadata_2025 huggingface dataset:
I own this language that everybody speaks
Authors: Ofori Dominic Maximilian , Albakry Mohammed
Published: July 2012

Based on interviews conducted in ten Catholic churches of the Ghanaian capital, Accra, the paper offers a profile of English use in Ghana and reports on the attitudes of Ghanaians toward English as the official language of their country. The results reveal the influential role English plays in the different settings of Ghanaian communication as well as the high esteem afforded to the English language by the majority of Ghanaian respondents. Most of them cited the numerous benefits that English, as a language of wider communication, brings to the individual speaker and the country.
Ascending kinship terminology in Middle Rocky Mountain English
Authors: Antieau Lamont D.
Published: July 2012

This study uses the tools of corpus linguistics to investigate ascending kinship terminology in the Linguistic Atlas of the Middle Rockies, a collection of interviews gathered in Colorado, Utah, and Wyoming as part of a dialectological survey of the American West. Relying in part on the framework of Dahl and Koptjevskaja-Tamm (2001), particularly with respect to their notion of a parental kin prototype, the study examines lexical and grammatical variation in the use of terms for parents and grandparents in different interviewing contexts in an effort to identify patterns in these distributions. The study finds important quantitative differences in the distribution of mother and father, as well as differences in the grammatical behavior of these and other kinship variants. While these results provide some support for a parental kin prototype, they also suggest the benefits that survey data collected within a variationist framework offer such a prototype, both with respect to the counterexamples to broad generalizations that such datasets inevitably include as well as the variable patterns that often emerge from such data that might go unobserved using formal methods.
Functions of epistolary formulae in Dutch letters from the seventeenth and eighteenth centuries
Authors: Rutten Gijsbert , van der Wal Marijke J.
Published: July 2012

Wray (2002) distinguishes three main functions of formulaic language relating to processing, interaction and discourse marking. In this paper, we show that Wray’s analysis of the functions of formulaic language also applies to historical letter-writing in a corpus of seventeenth- and eighteenth-century Dutch letters. Discourse is marked with formulae indicating the text type or the text structure. Interaction is covered by intersubjective formulae communicating health, greetings, wishes for renewed contact, as well as Christian-ritual formulae. The processing function is operationalised in terms of literacy and writing experience, assuming that the use of prefabricated formulae reduces the writing effort. Therefore, we expect less-experienced letter-writers to use more formulae than more-experienced writers. We will show that less-experienced writers are indeed more likely to use epistolary formulae, and conclude that Wray’s “reduction of the speaker’s processing effort” in online speech production, also applies to written seventeenth- and eighteenth-century Dutch.
The establishment of quantifier constructions for size nouns
Authors: Brems Lieselotte
Published: July 2012

Based on exhaustive diachronic corpus data, this paper determines the relative chronology in which the size nouns heap(s) and lot(s) have developed quantifier uses within NP of NP-syntagms, as in heaps / a lot of people. Using a constructional approach, it is claimed that size nouns occur in three distinct constructions or form–meaning pairings identified on the basis of systematic syntactic, semantico-pragmatic and collocational features. I argue that in order to establish which size noun was first to develop a quantifier use, we have to analyse diachronic data sets in terms of three constructions, viz. lexical head, partitive and quantifier constructions. In doing so, I will argue against the claim that heap developed its quantifier use first, around 1300, while lot developed one only around 1800. I will show that heap and lot(s) appear in an early partitive construction, c1300 and c1200, respectively, in which they are head nouns and have a collective sense. The quantifier construction in which heap(s) and lot(s) have modifier status and assess quantity similar to canonical quantifier many/much appears around the same time for both, viz. c1780.
On the relationship between subjectification, grammaticalisation and constructions
Authors: Loureiro-Porto Lucía
Published: July 2012

The terms subjectification, intersubjectification and construction are very often used in relation to grammaticalisation, although the relationship between them is not always clear. Subjectification is said to occur both within grammaticalisation and out of it. Constructions, in turn, have recently been found to play a key role in grammaticalisation, to the point that it is now generally accepted that before an item is grammaticalised the construction in which it appears will first develop a grammatical function. The relationship between construction and subjectification has not been addressed directly, even though an important number of the examples of subjectification found in the literature are explained in terms of constructions in which the subjectifying element occurs. This paper aims to shed more light on how subjectification, grammaticalisation and constructions are related in the history of English, by paying special attention to verbs and verbo-nominal expressions of necessity from Old to Early Modern English. The findings will show that, in these items, the interrelationship between subjectification and grammaticalisation is not direct; that subjectification need not be unidirectional; and that constructions involving necessity items are the source of subjectification.
Lexico-grammatical portraits of vulnerable women in war
Authors: MacLeod Nicci , Fennell Barbara A.
Published: July 2012

The 1641 Depositions are testimonies collected from (mainly Protestant) witnesses documenting their experiences of the Irish uprising that began in October 1641. As news spread across Europe of the events unfolding in Ireland, reports of violence against women became central to the ideological construction of the barbarism of the Catholic rebels. Against a backdrop of women’s subordination and firmly defined gender roles, this article investigates the representation of women in the Depositions, creating what we have termed “lexico-grammatical portraits” of particular categories of woman. In line with other research dealing with discursive constructions in seventeenth-century texts, a corpus-assisted discourse analytical approach is taken. Adopting the assumptions of Critical Discourse Analysis, the discussion is extended to what the findings reveal about representations of the roles of women, both in the reported events and in relation to the dehumanisation of the enemy in atrocity propaganda more generally.
So ADJ/ADV that clause patterns in Early Modern English medical writing
Authors: Hiltunen Turo
Published: July 2012

This paper investigates how an intensifying phraseological pattern involving the adverb so followed by a delayed declarative content clause is used in medical English in the early modern period (1500–1700). So may occur with adjectival, nominal or adverbial heads, and the pattern is used for indicating degree, extent or manner. The analysis employs the recently published Early Modern English Medical Texts corpus to show (i) that the pattern was in use throughout the entire period, (ii) that it tends to be more frequently used in learned rather than popular texts, and (iii) that it is typically used for giving descriptions and less often in instructions.
Structural and magnetic properties of Fe2CoGa Heusler nanoparticles
Authors: Wang Changhai , Casper Frederick , Gasi Teuta , Ksenofontov Vadim , Balke Benjamin , Fecher Gerhard H , Felser Claudia , Hwu Yeu-Kuang , Lee Jeu-Jau
Published: July 2012

Fe2CoGa Heusler nanoparticles are synthesized by a chemical method. The structure and magnetic properties of Fe2CoGa Heusler nanoparticles are investigated by x-ray diffraction, extended x-ray absorption fine structure and Mössbauer spectroscopy. The crystal structure of Fe2CoGa nanoparticles is described by the X-type structure (prototype: Li2AgSb). Magnetic measurements reveal the presence of small Fe2CoGa nanoparticles and lower magnetic moments compared with the theoretically predicted values.
Modelling of time-dependent dielectric barrier breakdown mechanisms in MgO-based magnetic tunnel junctions
Authors: Amara-Dababi S , Bea H , Sousa R , Mackay K , Dieny B
Published: July 2012

An investigation of barrier endurance till electrical breakdown in MgO-based magnetic tunnel junctions (MTJs) is presented. Samples were tested under pulsed electrical stress. By studying the effect of delay between successive pulses, an optimum endurance of MTJs is observed for an intermediate value of delay between pulses corresponding to an optimum trade-off between the average density of charge trapped in the barrier and the amplitude of its time-modulation at each voltage pulse. A charge trapping–detrapping model was developed which shows good coherence with experimental results. The influence of the delay between pulses on the trapped charge density in the tunnel barrier and on its time-modulation is discussed. The average density of trapped charges and its time-modulation are, respectively, responsible for a static and dynamic stress within the tunnel barrier, both leading to breakdown. The probability of breakdown of the MTJ for different applied pulse conditions has been evaluated. The expected endurance of the MTJs was deduced depending on the characteristics of the electrical stress in terms of delay, and unipolarity versus bipolarity. The study emphasizes the role of electron trapping/detrapping mechanisms on the tunnel barrier reliability. It also shows that extremely long endurance could be obtained in MTJs by reducing the density of electron trapping sites in the tunnel barrier.
Study of the high fuelling efficiency features of supersonic molecular beam injection
Authors: Yu D.L. , Chen C.Y. , Yao L.H. , Dong J.Q. , Feng B.B. , Zhou Y. , Shi Z.B. , Zhou J. , Han X.Y. , Zhong W.L. , Cui C.H. , Huang Y. , Cao Z. , Liu Yi , Yan L.W. , Yang Q.W. , Duan X.R. , Liu Yong
Published: July 2012

Features of high fuelling efficiency of supersonic molecular beam injection (SMBI) are studied on the HL-2A tokamak. Normalized by fuelled particle inventory, the D
α
emission induced by SMBI is about 50% higher than that of gas puffing (GP), indicating that a higher percentage of fuel injected by SMBI will enter the plasma. Strong particle convection (inward pinch) is observed with a hydrogen cyanide (HCN) interferometer as the densities from the core and edge channels increase and decrease, respectively, in the post-fuelling phase. In addition, microwave reflectometry indicates that the peak of fuelled density moves inward. By comparing the SMBI pulses with and without electron cyclotron resonance heating, it is identified that the pinch is driven by the enhancement of electron temperature gradient. Higher enhancement (up to twice) of the normalized electron temperature gradient is observed for SMBI than for GP, and this is another mechanism for the higher fuelling efficiency of SMBI.
Fabrication of micro pneumatic valves with double-layer elastic poly(dimethylsiloxane) membranes in rigid poly(methyl methacrylate) microfluidic chips
Authors: Huang Shanshi , He Qiaohong , Hu Xianqiao , Chen Hengwu
Published: July 2012

This paper presents a novel method to fabricate a normally open micro pneumatic valve in rigid poly(methyl methacrylate) (PMMA) chips. The control and fluid substrates of the valve were prepared with PMMA sheets via hot embossing. After both control and fluid substrates were silanized with 3-aminopropyltriethoxysilane and treated with glow discharge plasma, each of them was irreversibly bonded to a plasma-treated PDMS membrane, forming a control half or a fluid half. Relying on the native adhesive force of the PDMS membrane, the control half and fluid half were then reversibly sealed to form a full microchip with the four-layer structure of PMMA-PDMA ⋅  ⋅  ⋅ PDMS-PMMA. The irreversible bonding between rigid PMMA substrate and elastic PDMS membrane in combination with the reversible sealing between the control half and fluid half not only eases the difficulties in chip bonding, but also allows the control half and fluid half to be replaced individually in routine analyses. The performance of the developed micro pneumatic valves was characterized, and potential applications of the valves in droplet generation and micro flow injection analysis were demonstrated.
OmegaPlus: a scalable tool for rapid detection of selective sweeps in whole-genome datasets
Authors: Alachiotis N. , Stamatakis A. , Pavlidis P.
Published: July 2012

Summary: Recent advances in sequencing technologies have led to the rapid accumulation of molecular sequence data. Analyzing whole-genome data (as obtained from next-generation sequencers) from intra-species samples allows to detect signatures of positive selection along the genome and therefore identify potentially advantageous genes in the course of the evolution of a population.

We introduce OmegaPlus, an open-source tool for rapid detection of selective sweeps in whole-genome data based on linkage disequilibrium. The tool is up to two orders of magnitude faster than existing programs for this purpose and also exhibits up to two orders of magnitude smaller memory requirements.

Availability: OmegaPlus is available under GNU GPL at http://www.exelixis-lab.org/software.html.

Contact: n.alachiotis@gmail.com, pavlidisp@gmail.com

Supplementary information:  Supplementary data are available at Bioinformatics online.
AraPath: a knowledgebase for pathway analysis in Arabidopsis
Authors: Lai Liming , Liberzon Arthur , Hennessey Jason , Jiang Gaixin , Qi Jianli , Mesirov Jill P. , Ge Steven X.
Published: July 2012

Summary: Studying plants using high-throughput genomics technologies is becoming routine, but interpretation of genome-wide expression data in terms of biological pathways remains a challenge, partly due to the lack of pathway databases. To create a knowledgebase for plant pathway analysis, we collected 1683 lists of differentially expressed genes from 397 gene-expression studies, which constitute a molecular signature database of various genetic and environmental perturbations of Arabidopsis. In addition, we extracted 1909 gene sets from various sources such as Gene Ontology, KEGG, AraCyc, Plant Ontology, predicted target genes of microRNAs and transcription factors, and computational gene clusters defined by meta-analysis. With this knowledgebase, we applied Gene Set Enrichment Analysis to an expression profile of cold acclimation and identified expected functional categories and pathways. Our results suggest that the AraPath database can be used to generate specific, testable hypotheses regarding plant molecular pathways from gene expression data.

Availability:  http://bioinformatics.sdstate.edu/arapath/

Contact:  gexijin@gmail.com

Supplementary Information:  Supplementary data are available at Bioinformatics online.
Peeling Back the Layers: Vidalia Onions and the Making of a Global Agribusiness
Authors: Olsson Tore C.
Published: July 2012

In Depression-era South Georgia, truck farmers experimenting with onion planting found that their crop emerged unusually sweet, due to the region's climate and particular soil content. But what gave Vidalia onions a unique flavor—their low sulfur and high water content—also rendered them nearly impossible to market, as the vegetable spoiled much quicker than regular onions. In their seventy-year quest to overcome the onion's natural limitations, Georgia growers would transform their formerly insular region into a hub of global supermarket capitalism. As onion acreage skyrocketed with the advent of controlled atmosphere storage, growers recruited thousands of Latin American workers. Then, when storage techniques proved imperfect, industry leaders contracted with growers across Central and South America to produce sweet onions for sale during Georgia's off-season. In striking contrast to the Vidalia onion's branding as a “down-home” southern crop, the vegetable's history reveals the contradictions in our modern food system.
Progression of left atrial volume index in a population at risk for heart failure: a substudy of the STOP‐HF (St Vincent's Screening TO Prevent Heart Failure) trial
Authors: Collier Patrick , Watson Chris J. , Waterhouse Deidre F. , Dawkins Ian R. , Patle Anil K. , Horgan Stephen , Conlon Carmel M. , O'Hanlon Rory , Baugh John A. , Ledwidge Mark T. , McDonald Kenneth
Published: July 2012

Aims

Limited data are available concerning the evolution of the left atrial volume index (LAVI) in pre‐heart failure (HF) patients. The aim of this study was to investigate clinical characteristics and serological biomarkers in a cohort with risk factors for HF and evidence of serial atrial dilatation.

Methods and results

This was a prospective substudy within the framework of the STOP‐HF cohort (NCT00921960) involving 518 patients with risk factors for HF electively undergoing serial clinical, echocardiographic, and natriuretic peptide assessment. Mean follow‐up time between assessments was 15 ± 6 months. ‘Progressors’ (n = 39) were defined as those with serial LAVI change ≥3.5 mL/m2 (and baseline LAVI between 20 and 34 mL/m2). This cut‐off was derived from a calculated reference change value above the biological, analytical, and observer variability of serial LAVI measurement. Multivariate analysis identified significant baseline clinical associates of LAVI progression as increased age, beta‐blocker usage, and left ventricular mass index (all P < 0.05). Serological biomarkers were measured in a randomly selected subcohort of 30 ‘Progressors’ matched to 30 ‘Non‐progressors’. For ‘Progressors’, relative changes in matrix metalloproteinase 9 (MMP9), tissue inhibitor of metalloproteinase 1 (TIMP1), and the TIMP1/MMP9 ratio, markers of interstitial remodelling, tracked with changes in LAVI over time (all P < 0.05).

Conclusion

Accelerated LAVI increase was found to occur in up to 14% of all pre‐HF patients undergoing serial echocardiograms over a relatively short follow‐up period. In a randomly selected subcohort of ‘Progressors’, changes in LAVI were closely linked with alterations in MMP9, TIMP1, and the ratio of these enzymes, a potential aid in highlighting this at‐risk group.
Angiotensin receptor blockers and outcomes in real‐world older patients with heart failure and preserved ejection fraction: a propensity‐matched inception cohort clinical effectiveness study
Authors: Patel Kanan , Fonarow Gregg C. , Kitzman Dalane W. , Aban Inmaculada B. , Love Thomas E. , Allman Richard M. , Gheorghiade Mihai , Ahmed Ali
Published: July 2012

Aims

To examine the clinical effectiveness of angiotensin receptor blockers (ARBs) in older patients with heart failure and preserved ejection fraction (HF‐PEF).

Methods and results

Of the 10 570 hospitalized HF‐PEF patients, aged ≥65 years, EF ≥40%, in OPTIMIZE‐HF (2003–2004), linked to Medicare data (up to 31 December 2008), 3806 were not receiving angiotensin‐converting enzyme inhibitors or prior ARB therapy. Of these, 303 (8%) patients received new discharge prescriptions for ARBs. Propensity scores for the receipt of ARBs, estimated for each of the 3806 patients, were used to assemble a cohort of 296 pairs of patients receiving and not receiving ARBs, who were balanced on 114 baseline characteristics. Patients had a mean age of 80 years, mean EF of 55%, 69% were women, and 12% were African American. During 6 years of follow‐up, the primary composite endpoint of all‐cause mortality or HF hospitalization occurred in 79% (235/296) and 81% (241/296) of patients receiving and not receiving ARBs, respectively [hazard ratio (HR) associated with ARB use 0.88, 95% confidence interval (CI) 0.74–1.06; P = 0.179]. ARB use had no association with individual endpoints of all‐cause mortality (HR 0.93, 95% CI 0.76–1.14; P = 0.509), HF hospitalization (HR 0.90, 95% CI, 0.72–1.14; P = 0.389), or all‐cause hospitalization (HR 0.91, 95% CI 0.77–1.08; P = 0.265). These associations remained unchanged when we compared any (prevalent and new prescriptions) ARB use vs. non‐use in a separately assembled propensity‐matched cohort of 1137 pairs of HF‐PEF patients.

Conclusions

In real‐world older HF‐PEF patients, ARB use was not associated with improved clinical outcomes.
Rapid Onset of Specific Diaphragm Weakness in a Healthy Murine Model of Ventilator-induced Diaphragmatic Dysfunction
Authors: Mrozek Segolene , Jung Boris , Petrof Basil J. , Pauly Marion , Roberge Stephanie , Lacampagne Alain , Cassan Cécile , Thireau Jerome , Molinari Nicolas , Futier Emmanuel , Scheuermann Valerie , Michel Constantin Jean , Matecki Stefan , Jaber Samir
Published: July 2012

Background

Controlled mechanical ventilation is associated with ventilator-induced diaphragmatic dysfunction, which impedes weaning from mechanical ventilation. To design future clinical trials in humans, a better understanding of the molecular mechanisms using knockout models, which exist only in the mouse, is needed. The aims of this study were to ascertain the feasibility of developing a murine model of ventilator-induced diaphragmatic dysfunction and to determine whether atrophy, sarcolemmal injury, and the main proteolysis systems are activated under these conditions.

Methods

Healthy adult male C57/BL6 mice were assigned to three groups: (1) mechanical ventilation with end-expiratory positive pressure of 2-4 cm H2O for 6 h (n=6), (2) spontaneous breathing with continuous positive airway pressure of 2-4 cm H2O for 6 h (n=6), and (3) controls with no specific intervention (n=6). Airway pressure and hemodynamic parameters were monitored. Upon euthanasia, arterial blood gases and isometric contractile properties of the diaphragm and extensor digitorum longus were evaluated. Histology and immunoblotting for the main proteolysis pathways were performed.

Results

Hemodynamic parameters and arterial blood gases were comparable between groups and within normal physiologic ranges. Diaphragmatic but not extensor digitorum longus force production declined in the mechanical ventilation group (maximal force decreased by approximately 40%) compared with the control and continuous positive airway pressure groups. No histologic difference was found between groups. In opposition with the calpains, caspase 3 was activated in the mechanical ventilation group.

Conclusion

Controlled mechanical ventilation for 6 h in the mouse is associated with significant diaphragmatic but not limb muscle weakness without atrophy or sarcolemmal injury and activates proteolysis.
Estimating eigenvalues of dynamical systems from time series with applications to predicting cardiac alternans
Authors: Petrie Adam , Zhao Xiaopeng
Published: July 2012

The stability of a dynamical system can be indicated by eigenvalues of its underlying mathematical model. However, eigenvalue analysis of a complicated system (e.g. the heart) may be extremely difficult because full models may be intractable or unavailable. We develop data-driven statistical techniques, which are independent of any underlying dynamical model, that use principal components and maximum-likelihood methods to estimate the dominant eigenvalues and their standard errors from the time series of one or a few measurable quantities, e.g. transmembrane voltages in cardiac experiments. The techniques are applied to predicting cardiac alternans that is characterized by an eigenvalue approaching −1. Cardiac alternans signals a vulnerability to ventricular fibrillation, the leading cause of death in the USA.
Mean-field evolution of open quantum systems: an exactly solvable model
Authors: Merkli M. , Berman G. P.
Published: July 2012

We consider quantum particles coupled to local and collective thermal quantum environments. The coupling is energy conserving, and the collective coupling is scaled in the mean-field way. There is no direct interaction between the particles. We show that an initially factorized state of the particles remains factorized at all times, in the limit of large particle number. Each single-particle factor evolves according to an explicit, nonlinear, dissipative and time-dependent Hartree–Lindblad equation. The model is exactly solvable; we do not make any weak coupling or any Markovian approximations, and our results are mathematically rigorous.
Regeneration ofDrosophilasensory neuron axons and dendrites is regulated by the Akt pathway involvingPtenand microRNAbantam
Authors: Song Yuanquan , Ori-McKenney Kassandra M. , Zheng Yi , Han Chun , Jan Lily Yeh , Jan Yuh Nung
Published: July 2012

Both cell-intrinsic and extrinsic pathways govern axon regeneration, but only a limited number of factors have been identified and it is not clear to what extent axon regeneration is evolutionarily conserved. Whether dendrites also regenerate is unknown. Here we report that, like the axons of mammalian sensory neurons, the axons of certainDrosophiladendritic arborization (da) neurons are capable of substantial regeneration in the periphery but not in the CNS, and activating the Akt pathway enhances axon regeneration in the CNS. Moreover, those da neurons capable of axon regeneration also display dendrite regeneration, which is cell type-specific, developmentally regulated, and associated with microtubule polarity reversal. Dendrite regeneration is restrained via inhibition of the Akt pathway in da neurons by the epithelial cell-derived microRNAbantambut is facilitated by cell-autonomous activation of the Akt pathway. Our study begins to reveal mechanisms for dendrite regeneration, which depends on both extrinsic and intrinsic factors, including the PTEN–Akt pathway that is also important for axon regeneration. We thus established an important new model system—the fly da neuron regeneration model that resembles the mammalian injury model—with which to study and gain novel insights into the regeneration machinery.
ZRANB3 is a structure-specific ATP-dependent endonuclease involved in replication stress response
Authors: Weston Ria , Peeters Hanneke , Ahel Dragana
Published: July 2012

To efficiently duplicate their genomic content, cells must overcome DNA lesions that interfere with processive DNA replication. These lesions may be removed and repaired, rather than just tolerated, to allow continuity of DNA replication on an undamaged DNA template. However, it is unclear how this is achieved at a molecular level. Here we identify a new replication-associated factor, ZRANB3 (zinc finger, RAN-binding domain containing 3), and propose its role in the repair of replication-blocking lesions. ZRANB3 has a unique structure-specific endonuclease activity, which is coupled to ATP hydrolysis. It cleaves branched DNA structures with unusual polarity, generating an accessible 3′-OH group in the template of the leading strand. Furthermore, ZRANB3 localizes to DNA replication sites and interacts with the components of the replication machinery. It is recruited to damaged replication forks via multiple mechanisms, which involve interactions with PCNA, K63–polyubiquitin chains, and branched DNA structures. Collectively, our data support a role for ZRANB3 in the replication stress response and suggest new insights into how DNA repair is coordinated with DNA replication to maintain genome stability.
Systematic elucidation and in vivo validation of sequences enriched in hindbrain transcriptional control
Authors: Burzynski Grzegorz M. , Reed Xylena , Taher Leila , Stine Zachary E. , Matsui Takeshi , Ovcharenko Ivan , McCallion Andrew S.
Published: July 2012

Illuminating the primary sequence encryption of enhancers is central to understanding the regulatory architecture of genomes. We have developed a machine learning approach to decipher motif patterns of hindbrain enhancers and identify 40,000 sequences in the human genome that we predict display regulatory control that includes the hindbrain. Consistent with their roles in hindbrain patterning, MEIS1, NKX6-1, as well as HOX and POU family binding motifs contributed strongly to this enhancer model. Predicted hindbrain enhancers are overrepresented at genes expressed in hindbrain and associated with nervous system development, and primarily reside in the areas of open chromatin. In addition, 77 (0.2%) of these predictions are identified as hindbrain enhancers on the VISTA Enhancer Browser, and 26,000 (60%) overlap enhancer marks (H3K4me1 or H3K27ac). To validate these putative hindbrain enhancers, we selected 55 elements distributed throughout our predictions and six low scoring controls for evaluation in a zebrafish transgenic assay. When assayed in mosaic transgenic embryos, 51/55 elements directed expression in the central nervous system. Furthermore, 30/34 (88%) predicted enhancers analyzed in stable zebrafish transgenic lines directed expression in the larval zebrafish hindbrain. Subsequent analysis of sequence fragments selected based upon motif clustering further confirmed the critical role of the motifs contributing to the classifier. Our results demonstrate the existence of a primary sequence code characteristic to hindbrain enhancers. This code can be accurately extracted using machine-learning approaches and applied successfully for de novo identification of hindbrain enhancers. This study represents a critical step toward the dissection of regulatory control in specific neuronal subtypes.
The Mediator Complex Subunit PFT1 Interferes with COP1 and HY5 in the Regulation of Arabidopsis Light Signaling
Authors: Klose Cornelia , Büche Claudia , Fernandez Aurora Piñas , Schäfer Eberhard , Zwick Eva , Kretsch Thomas
Published: July 2012

Arabidopsis (Arabidopsis thaliana) mutants hypersensitive to far-red light were isolated under a light program of alternating red and far-red light pulses and were named eid (for empfindlicher im dunkelroten Licht). The dominant eid3 mutant carries a missense mutation in a conserved domain of PHYTOCHROME AND FLOWERING TIME1 (PFT1), an important component of the plant mediator coactivator complex, which links promoter-bound transcriptional regulators to RNA polymerase II complexes. Epistatic analyses were performed to obtain information about the coaction between the mutated PFT1eid3 and positively and negatively acting components of light signaling cascades. The data presented here provide clear evidence that the mutation mainly enhances light sensitivity downstream of phytochrome A (phyA) and modulates phyB function. Our results demonstrate that the Mediator component cooperates with CONSTITUTIVE PHOTORMORPHOGENIC1 in the regulation of light responses and that the hypersensitive phenotype strictly depends on the presence of the ELONGATED HYPOCOTYL5 transcription factor, an important positive regulator of light-dependent gene expression. Expression profile analyses revealed that PFT1eid3 alters the transcript accumulation of light-regulated genes even in darkness. Our data further indicate that PFT1 regulates the floral transition downstream of phyA. The PFT1 missense mutation seems to create a constitutively active transcription factor by mimicking an early step in light signaling.
The effect of suxamethonium alone and its interaction with gallamine on the indirectly elicited tetanic and single twitch contractions of skeletal muscle in man during anaesthesia.
Authors: Sugai N , Hughes R , Payne JP
Published: July 2012

Simultaneous measurements of tetanic and single twitch contractions of the adductor politics muscle in man were made during neuromuscular blockade induced by suxamethonium (0.2 mg/kg) under nitrous oxide, oxygen and pentazocine anaesthesia. 2. After a suitable control period, suxamethonium (0.2 mg/kg) was given intravenously and the same dose was repeated 15 min later. After a further 15 min gallamine (0.2 mg/kg) was administered intravenously. When recovery from gallamine reached a plateau on the tetanic contraction recording a third injection of suxamethonium was given. 3. In most patients, suxamethonium (0.2 mg/kg) caused a partial blockade of the single twitch and complete blockade of the tetanic contraction. In every instance, the tetanic contraction was more depressed and recovered more slowly than the single twitch which not only recovered promptly but also showed overshoot. 4. After gallamine marked antagonism to suxamethonium block developed and this was greater with the single twitch than with the tetanic contractions. 5. Tetanic‐tension fade was observed after every injection of suxamethonium and the degree of fade was dependent on the frequency of the tetanic stimulation.
Errors of drug prescribing.
Authors: Tesh DE , Beeley L
Published: July 2012

Seven thousand five hundred and twenty‐six prescriptions written for eight hundred and forty patients in three hospital wards have been analysed for errors of drug use and errors of prescription writing. 2. According to the criteria adopted for this survey, more than 3% of prescriptions contained an error of drug use and more than 30% an error of prescription writing. 3. The incidence of adverse drug reactions, overdosage and undertreatment might be reduced by more careful prescribing.
Comparative trial of propranolol and practolol in hyperthyroidism.
Authors: Nelson JK , McDevitt DG
Published: July 2012

The possible role of practolol in the management of hyperthyroidism has been studied by comparing it with propranolol. 2. In a double‐blind cross‐over trial, propranolol (40 mg), practolol (120 mg) and a placebo four times daily for one week were compared in twenty‐one hyperthyroid patients by sequential analysis. 3. Judged by their effect on the symptoms and signs of thyrotoxicosis, both propranolol and practolol were significantly better than the placebo but no clear distinction could be made between the two active compounds. 4. Propranolol and practolol reduced heart rate by 24 and 17% respectively compared with placebo. 5. Patients generally preferred propranolol or practolol to placebo but this preference did not achieve significance with either drug. 6. Only in its effect on heart rate was practolol significantly inferior to propranolol, and it would appear to be a useful alternative to propranolol in the management of the peripheral manifestations of hyperthyroidism.
Comparison of the effects of acebutolol (Sectral) and practolol (Eraldin) on airways obstruction in asthmatics.
Authors: Skinner C , Palmer KN
Published: July 2012

The effects of oral practolol (Eraldin, I.C.I. Ltd) (300 mg) and acebutolol (Sectral, May & Baker Ltd) (300 mg) were compared in a placebo‐controlled, crossover study in ten asthmatics. 2. Pulse rate, forced expiratory volume in one second (FEV1) and specific airways conductance were measured before and after a bronchodilator and the same procedure was repeated after taking acebutolol, practolol or placebo. 3. A mean increase in resting airways obstruction and reduction in bronchodilator response were evident with both drugs. The differences were statistically significant only after acebutolol for the logarithm of specific conductance. Mean plasma levels of the two drugs were similar. The response to both drugs was similar in the same patient and unrelated to severity of asthma. Mean reduction in resting pulse rate was statisitcally greater after acebutolol compared with placebo but not after practolol compared with placebo. 4. In any individual the beta‐adrenoceptor blocking response is unpredictable and any beta‐adrenoceptor blocking drug must be used with extreme caution in asthmatics.
Pharmacokinetic and pharmacological studies with tolamolol in man.
Authors: Faulkner JK , Stopher DA , Walden R
Published: July 2012

Pharmacokinetic and physiological variables were measured in six healthy subjects after intravenous and oral administration of tolamolol. 2. After intravenous injection of tolamolol (20 mg), there was a biphasic decline both in plasma concentration and attenuation of maximum exercise tachycardia. First and second phase half‐lives of plasma concentration were 7 min and 2.5 h respectively. WReduction of maximum exercise tachycardia declined from 32 beats/min at 2 h to 19 beats/min at 8 hours. Clearance of tolamolol from blood ranged from 0.8‐ 1.41 min‐1. 3. After the oral administration of tolamolol (100 mg), the average volume of distribution was 220.1 and plasma concentration half‐ life 1.8 hours. After ten eight‐hourly doses of 100 mg there was no accumulation of tolamolol and the half‐life of plasma clearance was unchanged. 4. Hydroxytolamolol was detected in plasma in two of six subjects after oral tolamolol. 5. There was a significant positive correlation between reduction in maximum exercise heart rate and logarithm of plasma concentration of tolamolol after both oral and intravenous administration.
Hepatic drug‐oxidizing enzyme systems and urinary D‐glucaric acid excretion in patients with congestive heart failure.
Authors: Tokola O , Pelkonen O , Karki NT , Luoma P
Published: July 2012

Drug‐oxidizing enzyme systems in liver biopsy samples and the urinary excretion of D‐glucaric acid were studied in two different groups of patients with cardiac insufficiency. 2. In one group of six patients, the activities of drug‐metabolizing enzymes had decreased considerably as compared with the control values, but in four liver samples from patients treated with oral hypoglycaemic agents for their diabetes, activities were higher than in control samples from ten patients. 3. In the other group of seven patients, the urinary excretion of D‐glucaric acid (isolated by ion‐exchange chromatography) was 60% lower than in the control group of nine humans, whereas in four patients taking antiepileptic agents excretion rate was higher than control values. 4. Because the age distribution was markedly different between cardiac insufficiency and control groups, it is difficult to conclude, if the impairment of drug metabolism was a consequence of the old age or of the disease process. However, drug‐oxidizing enzyme systems seem to be inducible also in old age. 5. The results support further the opinion that the urinary excretion of D‐glucaric acid may be one useful index in assessing an individual's capacity to metabolize foreign compounds especially in the patients with lowered drug metabolizing capacity.
Phenylbutazone: a clinico‐pharmacological study in rheumatoid arthritis.
Authors: Brooks PM , Walker JJ , Dick WC
Published: July 2012

A clinical trial of phenylbutazone in high dose (300 mg daily) and low dose (50 mg daily) is presented. 2. By analysis of the data by different methods, significant differences in clinical efficacy were shown between the two therapeutic regimes. 3. A relationship between the clinical effect and plasma level of phenylbutazone was demonstrated. 4. Some problems in the interpretation of plasma level‐ clinical effect correlates are discussed.
The administration of cephradine to patients in renal failure.
Authors: Solomon AE , Briggs JD
Published: July 2012

Cephradine was given to two control and twenty subjects with varying degrees of renal failure. Serum levels at various times were recorded and side‐effects noted. Recommendations for dosage schedules for subjects with renal failure have been made.
Control of epilepsy with a single daily dose of phenytoin sodium.
Authors: Cocks DA , Critchley EM
Published: July 2012

Fifty‐three patients in an epileptic centre have been studied. All were receiving phenytoin and many were also receiving other antoconvulsant drugs. 2. Thirty‐six patients took part in a three month cross over study. There was no significant change in the frequency of epileptic seizures or in the late morning serum concentration of phenytoin when the treatemtn was changed from two to three spaced doses of phenytoin sodium/day to a single dose at 12.00 hours. 3. Seventeen patients acted as a control group. They received phenytoin sodium as two or three spaced doses/day throughout the study. There was no significant change in the frequency of epileptic seizures or in the late morning serum concentration of phenytoin between the first and second three month periods of observation. 4. It is concluded that the total daily dose of phenytoin sodium may be given once daily without reduction of the anticonvulsant effect.
The planning of a clinical trials workshop.
Authors: Marsh BT
Published: July 2012

The groundwork involved in the planning and running of a Clinical Trials Workshop using a computerized simulation exercise called ‘Instant Experience’ is described in detail. 2. Groups of six or seven students, each with an experienced tutor, are set the problem of designing a clinical trial protocol for a given drug. By using a computer programme, results can be generated for these designs according to pre‐set rules laid down by the organizers. 3. The game itself acts as a vehicle for emphasizing the practical and theoretical problems associated with clinical trials. Further valuable information can be imparted during the group discussion periods when the trial design is being developed and during analysis of the results. 4. Limitations of this type of workshop include the need for students to have a working knowledge of clinical medicine and pharmacology, the competence of the tutors and organizers and the technical problems associated with computers and a comparatively rigid computer programme. 5. The value of this type of workshop lies in its ability to allow students to apply themselves to practical problems in clinical trials and to make mistakes with no harm to the patient.
Evaluation of tolerance after continuous and prolonged oral administration of salbutamol to asthmatic patients.
Authors: Bhatia SP , Davies HJ
Published: July 2012

Salbutamol (8 mg) was administered twice daily as a sustained release formulation to twenty‐four asthmatic patients for up to four weeks under double‐blind conditions. 2. The ability of bronchial smooth muscle to respond was determined by monitoring the response to salbutamol (200 mug) administered by aerosol at set intervals three times a week. 3. There was no evidence of diminishing response during the study period. 4. It is concluded that tolerance to salbutamol does not occur at therapeutic dose levels and that clinical observations of tolerance may be due to other factors.
Preliminary assessment of flutiorex, a new anorectic drug, in man.
Authors: Giudicelli JF , Richer C , Berdeaux A
Published: July 2012

1 The effects of +/‐flutiorex, a new anorectic agent, on food intake, the sympathetic nervous system and the central nervous system were compared to those of fenfluramine and a placebo in a double‐blind trial involving six healthy volunteers. 2. Flutiorex exerts a singificant anorectic effect and was shown to be approximately twice as potent as fenfluramine in this regard. 3 Flutiorex induces a definite alpha‐ adrenergic sympathomimetic stimulation as was shown by a rise in systolic blood pressure and the development of marked mydriasis. 4 Flutiorex is a central nervous system stimulant producing an increase in critical flicker frequency. It does not, however, influence psychomotor coordination as reflected in the pursuit rotor test. 5 Serial determinations of blood and urine levels of flutiorex and its deethylated metabolite, norflutiorex, showed that flutiorex is rapidly absorbed and deethylated, accumulates in large quantities in the tissues and, like its metabolite, is excreted in the urine in very small quantities. Blood levels of norflutiorex appear to remain elevated longer than those fo flutiorex.
The pharmacokinetics of ephedrine after oral dosage in asthmatics receiving acute and chronic treatment.
Authors: Pickup ME , May CS , Ssendagire R , Paterson JW
Published: July 2012

1 Ephedrine plasma levels have been measured in ten asthmatic patients given a singel dose of ephedrine hydrochloride (22 mg) along and in combination with theophylline and a barbiturate. 2 Pharmacokinetic assessment of the data indicated no significant intra‐subject changes in kinetic parameters before or after chronic treatment with ephedrine HCl (11 mg three times a day) alone or in combination. 3 Tolerance to these therapeutic doses, if it occurs, is therefore not disposition‐ related but rather to pharmacodynamic changes.
Simultaneous quantitative gas‐chromatographic analysis of ethosuximide, phenobarbitone, primidone and diphenylhydantoin.
Authors: Latham AN , Varlow G
Published: July 2012

1 Therapeutic serum concentrations of ethosuximide, phenobarbitone, primidone, and dipheylhydantoin were assayed from 1 ml of human serum. The extraction procedure was common to all four drugs and three internal standards. 2 Subsequent isothermal gas chromatographic analysis of serum extracts produced well resolved peaks for the underivatized quantitation of ethosuximide and phenobarbitone. Primidone and diphenylhydantoin were determined as methylated derivatives. 3 Mean coefficients of variation for the assay of each drug were less 7% on a newly packed and conditioned column and less than 10% after the technique had been in continuous use for 3 months. 4 The advantage of quantitation relative to peak area ratios rather than peak height ratios was minimal for the determination of ethosuximide, primidone and diphenylhydantoin but appeared significant for the assay of phenobarbitone.
Mesoridazine and human sleep.
Authors: Adam K , Allen S , Carruthers‐Jones I , Oswald I , Spence M
Published: July 2012

1 Mesoridazine, a phenothiazine of short half‐life, and potentially useful as an hypnotic, has here been investigated using volunteers of late middle age. 2 The electrophsiological recording of all‐night sleep was studied in seven subjects for a 7‐week period during which ther received mesoridazine (10 mg nightly) for 3 weeks. The drug reduced the frequency of transitions into wakefulness and stage 1 (drowsiness) and reduced the time spent in stage 1; there was a withdrawal rebound. Mesoridazine increased REM sleep above baseline levels and a rebound fall below baseline occurred on withdrawal. The drug did not alter the amount of stage 3 + 4 slow wave sleep. 3 Subjective self‐ratings were assessed in a 6‐week study of sixteen subjects. Sleep quality improved on mesoridazine (10 mg nightly) but there was diminution of zest and freshness 20 min after rising. Daytime concentration and anxiety were rated as not affected either by administration or withdrawal.
Anxiety and sleep after fosazepam.
Authors: Allen S , Oswald I
Published: July 2012

1 Six volunteers of mean age 59 years received placebo for week, then fosazepam (60 mg) nightly for 3 weeks, then placebo for 3 weeks. Subjective ratings and all‐night electrophysiological recordings were made. 2 Fosazepam administration improved subjective sleep quality nut impaired feelings of morning vitality. Its withdrawal was associated with anxiety, impaired concentration and continuing impairment of morning vitality. Measured sleep duration increased on fosazepam, sleep was less broken, slow wave sleep stages 3 and 4 diminished in duration and so did REM sleep. 3 Despite the short‐life of fosazepam some drug effects persisted for several days after withdrawal, suggesting action of a long half‐life metabolite.
Renal function, protein binding and pharmacological response to diazoxide.
Authors: Pearson RM , Breckenridge AM
Published: July 2012

1 The effect of rapid (10s) injections of diazoxide was studied in ten hypertensive patients with varying degrees of impairment of renal function. 2 There was a significant correlation between the patient's plasma urea concentration and reduction in mean arterial blood pressure. Diazoxide was also shown to be less highly protein bound in patients with renal failure. 3 It is suggested that the explanation for the increased hypotensive effect of diazoxide observed in patients with reduced renal function is related to higher unbound drug concentrations.