bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fragment-based identification of druggable ‘hot spots’ of proteins using Fourier domain correlation techniques
Authors: Brenke Ryan , Kozakov Dima , Chuang Gwo-Yu , Beglov Dmitri , Hall David , Landon Melissa R. , Mattos Carla , Vajda Sandor 
Published: January 2009

Abstract
Motivation: The binding sites of proteins generally contain smaller regions that provide major contributions to the binding free energy and hence are the prime targets in drug design. Screening libraries of fragment-sized compounds by NMR or X-ray crystallography demonstrates that such ‘hot spot’ regions bind a large variety of small organic molecules, and that a relatively high ‘hit rate’ is predictive of target sites that are likely to bind drug-like ligands with high affinity. Our goal is to determine the ‘hot spots’ computationally rather than experimentally.
Results: We have developed the FTMAP algorithm that performs global search of the entire protein surface for regions that bind a number of small organic probe molecules. The search is based on the extremely efficient fast Fourier transform (FFT) correlation approach which can sample billions of probe positions on dense translational and rotational grids, but can use only sums of correlation functions for scoring and hence is generally restricted to very simple energy expressions. The novelty of FTMAP is that we were able to incorporate and represent on grids a detailed energy expression, resulting in a very accurate identification of low-energy probe clusters. Overlapping clusters of different probes are defined as consensus sites (CSs). We show that the largest CS is generally located at the most important subsite of the protein binding site, and the nearby smaller CSs identify other important subsites. Mapping results are presented for elastase whose structure has been solved in aqueous solutions of eight organic solvents, and we show that FTMAP provides very similar information. The second application is to renin, a long-standing pharmaceutical target for the treatment of hypertension, and we show that the major CSs trace out the shape of the first approved renin inhibitor, aliskiren.
Availability: FTMAP is available as a server at http://ftmap.bu.edu/.
Contact: vajda@bu.edu
Supplementary information: Supplementary Material is available at Bioinformatics online.
Chronic obstructive pulmonary disease is an independent predictor of death but not atherosclerotic events in patients with myocardial infarction: analysis of the Valsartan in Acute Myocardial Infarction Trial (VALIANT)
Authors: Hawkins Nathaniel M. , Huang Zhen , Pieper Karen S. , Solomon Scott D. , Kober Lars , Velazquez Eric J. , Swedberg Karl , Pfeffer Marc A. , McMurray John J.V. , Maggioni Aldo P. ,   for the Valsartan in Acute Myocardial Infarction Trial Investigators
Published: January 2009

AimsChronic obstructive pulmonary disease is an independent predictor of mortality in patients with myocardial infarction (MI). However, the impact on mode of death and risk of atherosclerotic events is unknown.Methods and resultsWe assessed the risk of death and major cardiovascular (CV) events associated with chronic obstructive pulmonary disease in 14 703 patients with acute MI enrolled in the Valsartan in Acute Myocardial Infarction (VALIANT) trial. Cox proportional hazards models were used to evaluate the relationship between chronic obstructive pulmonary disease and CV outcomes. A total of 1258 (8.6%) patients had chronic obstructive pulmonary disease. Over a median follow‐up period of 24.7 months, all‐cause mortality was 30% in patients with chronic obstructive pulmonary disease, compared with 19% in those without. The adjusted hazard ratio (HR) for mortality was 1.14 (95% confidence interval 1.02–1.28). This reflected increased incidence of both non‐CV death [HR 1.86 (1.43–2.42)] and sudden death [HR 1.26 (1.03–1.53)]. The unadjusted risk of all pre‐specified CV outcomes was increased. However, after multivariate adjustment, chronic obstructive pulmonary disease was not an independent predictor of atherosclerotic events [MI or stroke: HR 0.98 (0.77–1.23)]. Mortality was significantly lower in patients receiving beta‐blockers, irrespective of airway disease.ConclusionIn high‐risk patients with acute MI, chronic obstructive pulmonary disease is associated with increased mortality and non‐fatal clinical events (both CV and non‐CV). However, patients with chronic obstructive pulmonary disease did not experience a higher rate of atherosclerotic events.
Clonidine and Dexmedetomidine Produce Antinociceptive Synergy in Mouse Spinal Cord
Authors: Fairbanks Carolyn A. , Kitto Kelley F. , Nguyen H Oanh , Stone Laura S. , Wilcox George L. 
Published: January 2009

Background
Synergy between drugs manifests with increased potency and/or efficacy of the combination relative to either agonist given alone. Synergy is typically observed between drugs of different classes, as is the case with the alpha-adrenergic-opioid receptor synergy often observed in preclinical studies. However, rare studies report synergy between agonists of the same class. The current study examined the analgesic interaction between two intrathecally injected alpha2-adrenergic receptor (AR) agonists previously thought to act at the same receptor subtype when given spinally.

Methods
Mice were given clonidine, dexmedetomidine, or the combination spinally to evaluate the interaction between these two agonists. The ED50 values were calculated, and the interactions were tested by isobolographic analysis. The rotarod test was performed in the same mice after the completion of analgesic assessment to assess motor or sedative effects. These experiments were performed in outbred mice as well as in mice with mutant alpha2A ARs, alpha2C AR knockout mice, or wild-type controls. Finally, analgesic cross-tolerance between clonidine and dexmedetomidine was evaluated.

Results
Clonidine and dexmedetomidine interacted synergistically in all lines except the alpha2C AR knockout line, implicating alpha2C ARs in the interaction. In addition, clonidine and dexmedetomidine did not show analgesic cross-tolerance in the outbred strain, suggesting that the two drugs have distinct mechanisms of action.

Conclusions
The current study introduces a new synergistic agonist pair, clonidine-dexmedetomidine. These two drugs seem to require the alpha2A AR for spinal analgesia when given separately; when delivered as a combination, the resultant synergistic interaction requires the alpha2C AR as well.
Changing the Paradigm: Omegaven for the Treatment of Liver Failure in Pediatric Short Bowel Syndrome
Authors: Diamond Ivan R , Sterescu Anca , Pencharz Paul B , Kim Jae H , Wales Paul W 
Published: January 2009

ABSTRACTBackground:Parenteral omega‐3 fatty acids, such as Omegaven, may benefit patients with pediatric short bowel syndrome (SBS) who develop parenteral nutrition–associated liver disease (PNALD).Patients and Methods:Retrospective cohort describing the outcome of all 12 children with SBS and advanced PNALD who were treated with Omegaven (target omega‐6 to omega‐3 fatty acid ratio = 1:1 to 2:1).Results:The median age was 7.5 (range 3.6–46) months, and median parenteral nutrition duration before starting Omegaven was 28.4 (range 15.3–55.3) weeks. Median initial serum conjugated bilirubin was 137 (range 54–203) μmol/L (8.06 [3.18–11.94] mg/dL). Of the 12 patients, 9 had complete and sustained resolution of hyperbilirubinemia within a median of 24 (range 7–37) weeks, and all are no longer being considered for liver transplantation. Improvements in markers of hepatic inflammation as well as nutritional status also were noted in these patients. Three patients received a liver‐intestine transplant while taking Omegaven. There were no complications attributable to Omegaven.Conclusions:Omegaven is associated with restoration of liver function in patients with SBS and advanced liver disease. Parenteral omega‐3 fatty acids, such as Omegaven, have the potential to fundamentally alter the paradigm of neonatal SBS from one of early death or transplantation from liver failure to a more chronic disease. More children with SBS should achieve full enteral tolerance and those who do not have the capacity for intestinal adaptation should be able to survive and receive an intestinal graft when older.
Trichoderma virens, a Plant Beneficial Fungus, Enhances Biomass Production and Promotes Lateral Root Growth through an Auxin-Dependent Mechanism in Arabidopsis
Authors: Contreras-Cornejo Hexon Angel , Macías-Rodríguez Lourdes , Cortés-Penagos Carlos , López-Bucio José 
Published: January 2009

AbstractTrichoderma species belong to a class of free-living fungi beneficial to plants that are common in the rhizosphere. We investigated the role of auxin in regulating the growth and development of Arabidopsis (Arabidopsis thaliana) seedlings in response to inoculation with Trichoderma virens and Trichoderma atroviride by developing a plant-fungus interaction system. Wild-type Arabidopsis seedlings inoculated with either T. virens or T. atroviride showed characteristic auxin-related phenotypes, including increased biomass production and stimulated lateral root development. Mutations in genes involved in auxin transport or signaling, AUX1, BIG, EIR1, and AXR1, were found to reduce the growth-promoting and root developmental effects of T. virens inoculation. When grown under axenic conditions, T. virens produced the auxin-related compounds indole-3-acetic acid, indole-3-acetaldehyde, and indole-3-ethanol. A comparative analysis of all three indolic compounds provided detailed information about the structure-activity relationship based on their efficacy at modulating root system architecture, activation of auxin-regulated gene expression, and rescue of the root hair-defective phenotype of the rhd6 auxin response Arabidopsis mutant. Our results highlight the important role of auxin signaling for plant growth promotion by T. virens.
Development, validation and dissemination of instructional materials: an analysis
Authors: CREECH JANE C. , ARSHAM G. M. 
Published: January 2009

SummaryThis paper describes the activities of SIMO (Self‐Instructional Materials in Ophthalmology), a 2‐year project to develop four slide/tape units and one videocassette in basic ophthalmology for medical students,† The background of the project, some observations regarding pitfalls in the developmental process, data on product evaluation, and factors in effective dissemination are presented. Instructional effectiveness was documented using measures of knowledge, skill in recognizing abnormalities, and performance of diagnostic and management techniques.
Performance of women medical graduates from Medical College, Baroda, 1949–14
Authors: BHATT R. V. , SONI J. M. , PATEL N. F. 
Published: January 2009

SummaryWomen account for 15% of the total admissions in medicine. 271 women have graduated from Medical College, Baroda in 25 years. The examination results are better in women than in men. Obstetrics and gynaecology is the most common speciality selected by women. Job satisfaction is found in 87% of women. Unmarried women account for 15%, 66% have married a doctor and 19% are married to non‐ medical spouse. Emigration is to the extent of 39%.
Mycoplasma pneumoniae J‐domain protein required for terminal organelle function
Authors: Cloward Jason M. , Krause Duncan C. 
Published: January 2009

SummaryThe cell wall‐less prokaryote Mycoplasma pneumoniae causes tracheobronchitis and primary atypical pneumonia in humans. Colonization of the respiratory epithelium requires proper assembly of a complex, multifunctional, polar terminal organelle. Loss of a predicted J‐domain protein also having domains unique to mycoplasma terminal organelle proteins (TopJ) resulted in a non‐motile, adherence‐deficient phenotype. J‐domain proteins typically stimulate ATPase activity of Hsp70 chaperones to bind nascent peptides for proper folding, translocation or macromolecular assembly, or to resolve stress‐induced protein aggregates. By Western immunoblotting all defined terminal organelle proteins examined except protein P24 remained at wild‐type levels in the topJ mutant; previous studies established that P24 is required for normal initiation of terminal organelle formation. Nevertheless, terminal organelle proteins P1, P30, HMW1 and P41 failed to localize to a cell pole, and when evaluated quantitatively, P30 and HMW1 foci were undetectable in >40% of cells. Complementation of the topJ mutant with the recombinant wild‐type topJ allele largely restored terminal organelle development, gliding motility and cytadherence. We propose that this J‐domain protein, which localizes to the base of the terminal organelle in wild‐type M. pneumoniae, functions in the late stages of assembly, positioning, or both, of nascent terminal organelles.
Socio‐environmental predictors of Barmah forest virus transmission in coastal areas, Queensland, Australia
Authors: Naish Suchithra , Hu Wenbiao , Nicholls Neville , Mackenzie John S. , Dale Pat , McMichael Anthony J. , Tong Shilu 
Published: January 2009

SummaryObjective  To assess the socio‐environmental predictors of Barmah forest virus (BFV) transmission in coastal areas, Queensland, Australia.Methods  Data on BFV notified cases, climate, tidal levels and socioeconomic index for area (SEIFA) in six coastal cities, Queensland, for the period 1992–2001 were obtained from the relevant government agencies. Negative binomial regression models were used to assess the socio‐environmental predictors of BFV transmission.Results  The results show that maximum and minimum temperature, rainfall, relative humidity, high and low tide were statistically significantly associated with BFV incidence at lags 0–2 months. The fitted negative binomial regression models indicate a significant independent association of each of maximum temperature (β = 0.139, P = 0.000), high tide (β = 0.005, P = 0.000) and SEIFA index (β = −0.010, P = 0.000) with BFV transmission after adjustment for confounding variables.Conclusions  The transmission of BFV disease in Queensland coastal areas seemed to be determined by a combination of local social and environmental factors. The model developed in this study may have applications in the control and prevention of BFV disease in these areas.
Evolutionary lability of odour‐mediated host preference by the malaria vector Anopheles gambiae
Authors: Lefèvre Thierry , Gouagna Louis‐Clément , Dabire Kounbrobr Roch , Elguero Eric , Fontenille Didier , Costantini Carlo , Thomas Frédéric 
Published: January 2009

SummaryMany species of disease‐vector mosquitoes display vertebrate host specificity. Despite considerable progress in recent years in understanding the proximate and ultimate factors related to non‐random host selection at the interspecific level, the basis of this selection remains only partially understood. Anopheles gambiae sensu stricto, the main malaria vector in Africa, is considered a highly anthropophilic mosquito, and host odours have been shown to play a major role in the host‐seeking process of this species. Studies on host preference of An. gambiae have been either conducted in controlled conditions using laboratory reared mosquitoes and worn stockings as host‐related stimuli, or have been done in the field with methods that do not account for internal (e.g. age of sampled mosquitoes) and/or environmental effects. We explored differential behavioural responses to host odours between two populations of the same sibling species, An. gambiae in semi‐field conditions in Burkina Faso. The behavioural responses (i.e. degree of activation and strength of anemotaxis) were investigated using a Y‐olfactometer designed to accommodate whole hosts as a source of odour stimuli. Two strains of An. gambiae (3 to 4‐day‐old female) from laboratory Kisumu strain, and from field‐collected individuals were confronted to combinations of stimuli comprising calf odour, human odour and outdoor air. In dual‐choice tests, field mosquitoes chose human odour over calf odour, outdoor air over calf odour and responded equally to human and outdoor air, while laboratory mosquitoes responded equally to human and calf odour, human odour over outdoor air and calf odour over outdoor air. Overall, no effect of CO2 exhaled by humans and calves neither on the proportion of activated mosquitoes nor on the relative attractiveness to odour stimuli was found. We report for the first time an intraspecific variation in host‐odour responses. This study clearly suggests that there may be genetic polymorphism underlying host preference and emphasizes that the highly anthropophilic label given to An. gambiae s.s. must be carefully interpreted and refer to populations rather than the whole sibling species.
Different transmission strategies of a parasite in male and female hosts
Authors: FELLOUS S. , KOELLA J. C. 
Published: January 2009

AbstractWe investigated whether a parasite with two routes of transmission responds to the different transmission opportunities offered by male and female hosts by using different transmission strategies in the two sexes. The parasite Ascogregarina culicis, which infects the mosquito Aedes aegypti, can be transmitted as its host’s pupa transforms into an adult or when a female lays its eggs. As the latter transmission route is missing in males, we expected, and found, that the parasite releases a greater proportion of its infectious forms during emergence when it is within a male than when it infects a female. The transmission route, which influences the parasite’s dispersal and the evolution of its virulence, was also affected by the dose of infection and the parasite’s previous transmission route. Our results emphasize the complexity underlying the development of parasites and show their ability to tune their strategy to their environment.
Estimating the heritability of female lifetime fecundity in a locally adapted Drosophila melanogaster population
Authors: LONG T. A. F. , MILLER P. M. , STEWART A. D. , RICE W. R. 
Published: January 2009

AbstractThe heritability of genome‐wide fitness that is expected in finite populations is poorly understood, both theoretically and empirically, despite its relevance to many fundamental concepts in evolutionary biology. In this study, we used two independent methods of estimating the heritability of lifetime female fecundity (the predominant female fitness component in this population) in a large, outbred population of Drosophila melanogaster that had adapted to the laboratory environment for over 400 generations. Despite strong directional selection on adult female fecundity, we uncovered high heritability for this trait that cannot be explained by antagonistic pleiotropy with juvenile fitness. The evolutionary significance of this high heritability of lifetime fecundity is discussed.
Blood Supply in the Tongue of Nellore Bos indicus (Linnaeus, 1758)
Authors: Ferreira J. R. , Nogueira D. J. , Rodrigues B. F. , Alvarenga B. F. 
Published: January 2009

SummaryAspects of the vascularization of the tongue of Nellore Bos indicus (Linnaeus, 1758) were evaluated through the vascular injection technique (with latex‐type Neoprene 450, Du Pont do Brasil S.A. and Sulvinil coloring, Glassurit), fixed in formaldehyde at 7% and dissected with magnifying glass. The material was collected at Goiás Carnes Freezer Warehouse in Goiania, Goias. It was found that the deep lingual artery penetrated the lower lateral region of the prominence of the dorsal area of the tongue, advancing rostrally between the hyoid bone and the hypoglossal muscle. In the intravisceral initial third, the artery represents the deep, sinuous continuation branch of the lingual artery, in which path the sublingual artery was stressed in the ventral plan. Then, the artery deepened in the interior of the hypoglossal muscles and genioglossal, supplying dorsal branches (from three to nine) for the lingual torus; from one to five dorsal collateral branches for the lingual cavity; and one or two ventral collateral branches. At the lingual apex, the artery undergoes bifurcation supplying collateral, dorsal and ventral branches with anastomoses between the parallel vessels in the same antimere and between branches of lower caliber hierarchy between opposite antemeres. The large presence of microvessels indicates a significant blood supply to the organ. These results, in comparison with those found in literature, suggest a peculiar vascular pattern for this cattle breed of Indian origin.
Effects of Eavesdropping on Subsequent Signalling Behaviours in Male Canaries
Authors: Amy Mathieu , Leboucher Gérard 
Published: January 2009

AbstractSignalling interactions could provide information for an observing third party. This behaviour has been labelled as eavesdropping. Studies on eavesdropping in birds have concerned only few species and have mainly been conducted in the wild. Our experiment was designed to evaluate the effects of eavesdropping on subsequent interactions in male canaries in a controlled laboratory context. The experiment had two stages: a presentation stage and a test stage. During the presentation stage, subjects heard three different interaction types: an alternating interaction, an overlapping interaction or two song sequences presented separately one after the other, i.e. without interaction. Then during the test stage, subjects were allowed to listen to the songs previously heard separately. We noted calls emitted by subjects during the two stages. During the presentation stage, responses of male canaries did not differ according to the type of interaction they could hear. During the test stage, we found a clear effect of the song status on the calls emitted by subjects. They emitted less calls during the songs of the winner than during all other songs. Surprisingly, subjects also produced intermediate responses by emitting fewer calls during the second song previously heard during the presentation phase, and during the song of the looser when compared to the three other songs. Our results show that male canaries obtain information on the relative threat from an overlapping interaction whereas an alternating interaction does not seem to provide any kind of relative information on singers’ status. In following encounters, the higher the potential threat of a singer was, the less the subjects emitted calls, probably to avoid the more serious rival. This inhibiting effect is discussed.