bluuebunny/crossref_metadata_2025 huggingface dataset:
Increased thrombin activity following reperfusion after ischemic stroke alters synaptic transmission in the hippocampus
Authors: Bushi Doron , Ben Shimon Marina , Shavit Stein Efrat , Chapman Joab , Maggio Nicola , Tanne David
Published: September 2015

Thrombin, a key player in thrombogenesis, affects cells in the brain through activation of its receptors. Low levels of thrombin activity are protective while high levels are toxic. We sought to quantify thrombin activity levels and their spatial distribution in brains of mice following reperfusion after ischemic stroke focusing on infarct, peri‐infarct and contralateral areas. In order to find out the contribution of brain‐derived thrombin, mRNA levels of both prothrombin and factor X were determined. Furthermore, we assessed the effect of thrombin levels that were measured in the ischemic brain on synaptic transmission. We found that in the brains of mice following transient middle cerebral artery occlusion, thrombin activity is elevated throughout the ischemic hemisphere, including in peri‐infarct areas (90 ± 33 and 60 ± 18 mU/mL, in the infarct and peri‐infarct areas, respectively, compared to 11 ± 3 and 12 ± 5 mU/mL, in the corresponding contralateral areas; mean ± SE; p < 0.05). Brain mRNA levels of prothrombin and, in particular, factor X are up‐regulated in the ischemic core. Hippocampal slices treated with thrombin concentrations as found in the ischemic hemisphere show altered synaptic responses. We conclude that high thrombin activity following reperfusion after ischemic stroke may cause synaptic dysfunction.

image

Following transient middle cerebral artery occlusion in mice, thrombin activity is elevated throughout the ischemic hemisphere, including in peri‐infarct areas. Brain mRNA levels of prothrombin and factor X are up‐regulated in the ischemic core. Thrombin is known to affect synaptic function in a concentration dependent manner and hippocampal slices treated with the concentrations found in the ischemic hemisphere show altered synaptic responses. We conclude that in ischemic stroke, the high brain thrombin activity found after reperfusion may cause synaptic dysfunction.
Extensively remodeled, fractured cetacean tympanic bullae show that whales can survive traumatic injury to the ears
Authors: Yamato Maya , Khidas Kamal , Pyenson Nicholas D. , Fordyce R. Ewan , Mead James G.
Published: September 2015

Underwater human activities and anthropogenic noise in our oceans may be a major source of habitat degradation for marine life. This issue was highlighted by the opening of the United States Eastern Seaboard for seismic oil and gas exploration in 2014, which generated massive media coverage and widespread concern that seismic surveys could kill or deafen whales. We discovered 11 new specimens of fractured and healed cetacean ear bones, out of a survey of 2127 specimens housed in museum collections. This rare condition has been previously reported only in two specimens of blue whales (Balaenoptera musculus) from the early 1900s, summarized by Fraser & Purves (). All of our new specimens are represented by species for which this condition had never been reported previously, including both baleen and toothed whales. The baleen whale specimens (Balaenoptera physalus, Balaenoptera borealis, Balaenoptera acutorostrata) were collected during Canadian commercial whaling operations in the Atlantic Ocean in the 1970s; the specimens include ear bones with well‐healed fractures, demonstrating that baleen whales are capable of overcoming traumatic injury to the ears. The toothed whale specimens (Delphinus sp., Berardius bairdii) were found dead on beaches in 1972 and 2001, respectively, with less remodeled fractures. Thus, ear injuries may be more lethal to the echolocating toothed whales, which rely on hearing for navigation and foraging. We explore several hypotheses regarding how these injuries could have occurred, and conclude that the most parsimonious explanations appear to be both direct and indirect effects of lytic processes from disease or calcium depletion, or damage from external pressure waves. Although further research is required to confirm whether the fractures resulted from natural or human‐induced events, this study underscores the importance of museum collections and the work of stranding networks in understanding the potential effects of modern human activities on marine mammal health.
Longitudinal Links Between Discrimination and Civic Development Among Latino and Asian Adolescents
Authors: Ballard Parissa J.
Published: September 2015

The transition from adolescence to adulthood is formative for civic development. Unfortunately, many adolescents from Latino and Asian backgrounds experience discrimination, which can alienate them from civic life. This study employed cross‐lagged structural equation modeling to test the bidirectional links between perceived discrimination and civic beliefs and activism among Latino and Asian late adolescents (N = 400, Mage = 17.34, 61% female). Civic beliefs (i.e., believing that the government is unresponsive) and civic activism (i.e., protesting and expressing political opinions) in high school predicted increased perceptions of discrimination over time. Perceiving high levels of discrimination in high school predicted a decrease in the belief that society is fair over time.
Blood and Cerebrospinal Fluid α‐Tocopherol and Selenium Concentrations in Neonatal Foals with Neuroaxonal Dystrophy
Authors: Finno C.J. , Estell K.E. , Katzman S. , Winfield L. , Rendahl A. , Textor J. , Bannasch D.L. , Puschner B.
Published: September 2015

Background

Equine neuroaxonal dystrophy/equine degenerative myeloencephalopathy (NAD/EDM) is a neurodegenerative disorder affecting genetically predisposed foals maintained on α‐tocopherol (α‐TP)‐deficient diet.

Objective

Intramuscular α‐TPand selenium (Se) administration at 4 days of age would have no significant effect on serum or cerebrospinal fluid (CSF) α‐TPin healthy foals. Serum andCSFα‐TP, but not Se, would be significantly decreased inNAD/EDM‐affected foals during first year of life.

Animals

Fourteen Quarter horse foals; 10 healthy foals supplemented with 0.02 mL/kg injectable α‐TPandSe (n = 5) or saline (n = 5) at 4 days of age and 4 unsupplementedNAD/EDM‐affected foals.

Methods

Complete neurologic examinations were performed, blood andCSFwere collected before (4 days of age) and after supplementation at 10, 30, 60, 120, 180, 240, and 360 days of age. Additional blood collections occurred at 90, 150, 210, and 300 days. At 540 days,NAD/EDM‐affected foals and 1 unsupplemented healthy foal were euthanized and necropsies performed.

Results

Significant decreases in blood,CSFα‐TPandSe found in the first year of life in all foals, with most significant changes in serum α‐TPfrom 4–150 days. Dam α‐TPandSe significantly influenced blood concentrations in foals. Injection of α‐TPandSe did not significantly increaseCSF Se, blood orCSFα‐TPin healthy foals.NAD/EDM‐affected foals had significantly lowerCSFα‐TPthrough 120 days.

Conclusions and Clinical Importance

Injection of α‐TPandSe at 4 days of age does not significantly increase blood orCSFα‐TP. Despite all 14 foals remaining deficient in α‐TP, only the 4 genetically predisposed foals developedNAD/EDM.
Biofilm formation by pathogenic Prototheca algae
Authors: Kwiecinski J.
Published: September 2015

Prototheca microalgae are the only plants known to cause infections in humans and animals. The mechanisms of Prototheca infections are poorly understood, and no good treatments are available. Biofilms—surface-attached, three-dimensional microbial communities contributing to chronic infections—are formed by many pathogenic bacteria and fungi, but it is not known if Prototheca algae also have this ability. This study shows that various Prototheca species form biofilms composed of surface-attached cells in all growth phases, linked together by matrix containing DNA and polysaccharides. Biofilm formation was modulated by the presence of host plasma or milk. Compared to planktonic cells, Prototheca biofilms caused decreased release of IL-6 by mononuclear immune cells and responded differently to treatment with antimicrobials. Prototheca biofilms possibly contribute to chronic and hard-to-treat character of those algal infections.

Significance and Impact of the Study

Prototheca algae are the only existing pathogenic plants. Almost nothing is known about mechanisms of Prototheca infections. This study identifies that, similar to pathogenic bacteria and fungi, Prototheca algae can form biofilms. These biofilms induce reduced immune cell activation relative to planktonic cells, and are also less susceptible to antimicrobials. Biofilm formation by Prototheca could be the first in vitro correlate of pathogenicity, opening a new research field for this pathogen.
Norden multimesh gill net for fish sampling in lotic environments
Authors: Fjälling Arne , Degerman Erik , Johansson Ulf
Published: September 2015

Reliable data on species composition, length‐frequency distribution and relative density of freshwater fish are difficult to obtain for some stream habitats. Present methods, with electro‐fishing being the most important one, are not useful where the conditions are unfavourable, as in deep, turbulent or turbid waters. A new sampling method focusing on fish in stream habitats is presented in this study. The novel gill net is a development of the European standardized fish sampling method Norden (standardized multimesh survey net). The net was tested in both lotic (up to 0.5 m s−1) and lentic habitats. The results were compared to fish trap data. The novel net produced consistent data on the number of fish species and length frequency of the catch. It was straightforward to handle and is considered to be useful for sampling fish in flowing waters. Further studies are required to evaluate the performance of the net at high stream velocities, and to establish the effort (number of nets) required for good sample precision.
Development and application of a simulation model for reservoir management
Authors: Bhadra A. , Bandyopadhyay A. , Singh R. , Raghuwanshi N. S.
Published: September 2015

The success of irrigation system operation and planning depends on accurate quantification of supply and demand, and an equitable distribution of available water. The ultimate aim of this study was to determine how to meet the irrigation water demands if possible or to minimize the gap between the water supply and the demand. Most of the irrigation literature focuses only on the demand and the distribution aspects of this issue Irrigation projects that receive water from reservoirs, however, can be challenging to manage because the annual fluctuations in available water release from a reservoir can have a considerable impact on the irrigation management strategy. In real‐world situations, the reservoir operating rules guide reservoir operators in making actual water release decisions. This study develops a water balance simulation model for reservoir management, as well as testing it for Kangsabati Reservoir, West Bengal, India. Two rule curves for deciding irrigation water available from the reservoir were generated by taking the average and minimum stage values on a daily basis for a 16‐year period (1988–2003). Maintaining a minimum stage of 120.4 m throughout the year served as another rule to decide the release water available for irrigation. The minimum allowable stage of reservoir corresponding to a particular date of the year can be determined from those reservoir specific rule curves generated for irrigation purposes. The maximum permissible water release/outflow for irrigation from the test reservoir was taken as the volume of water available above the minimum allowable stage corresponding to the selected rule curve. The saturated hydraulic conductivity value (KS) was calibrated to be 4.31 mm day−1 for Kangsabati Reservoir.
Jihad in a World of Sovereigns: Law, Violence, and Islam in the Bosnia Crisis
Authors: Li Darryl
Published: September 2015

This article argues that jihads waged in recent decades by “foreign fighter” volunteers invoking a sense of global Islamic solidarity can be usefully understood as attempts to enact an alternative to the interventions of the “International Community.” Drawing from ethnographic and archival research on Arab volunteers who joined the 1992–1995 war in Bosnia‐Herzegovina, this article highlights the challenges and dilemmas facing such jihad fighters as they maneuvered at the edges of diverse legal orders, including international and Islamic law. Jihad fighters appealed to a divine authority above the global nation‐state order while at the same time rooting themselves in that order through affiliation with the sovereign and avowedly secular nation‐state of Bosnia‐Herzegovina. This article demonstrates an innovative approach to law, violence, and Islam that critically situates states and nonstate actors in relation to one another in transnational perspective.
Divide et impera: boundaries shape the plant body and initiate new meristems
Authors: Wang Quan , Hasson Alice , Rossmann Susanne , Theres Klaus
Published: September 2015

Boundaries, established and maintained in different regions of the plant body, have diverse functions in development. One role is to separate different cell groups, for example the differentiating cells of a leaf primordium from the pluripotent cells of the apical meristem. Boundary zones are also established during compound leaf development, to separate young leaflets from each other, and in many other positions of the plant body. Recent studies have demonstrated that different boundary zones share similar properties. They are characterized by a low rate of cell divisions and specific patterns of gene expression. In addition, the levels of the plant hormones auxin and brassinosteroids are down‐regulated in boundary zones, resulting in a low differentiation level of boundary cells. This feature seems to be crucial for a second important role of boundary zones, the formation of new meristems. The primary shoot meristem, as well as secondary and ectopic shoot meristems, initiate from boundary cells that exhibit competence for meristem formation.

Contents

Summary
485

I.
Introduction
485

II.
Development of boundary zones
486

III.
Boundaries shape the leaf
491

IV.
Boundary zones are launching pads for meristem formation
491

V.
Conclusions/future perspectives
495

Acknowledgements
495

References
495
Heritability of floral volatiles and pleiotropic responses to artificial selection in Brassica rapa
Authors: Zu Pengjuan , Blanckenhorn Wolf U. , Schiestl Florian P.
Published: September 2015

The evolution of the vast diversity of floral volatiles is little understood, although they serve fundamental functions, such as pollinator attraction and herbivore deterrence. Floral volatiles are often species specific, yet highly variable and sensitive to environmental factors. To date, nothing is known about the heritability of floral volatiles, and whether individual compounds can evolve independently or solely in concert with the whole volatile bouquet.

We conducted bi‐directional artificial selection on four target floral volatiles to estimate heritability and correlated pleiotropic responses in the wild turnip (Brassica rapa).

The realized heritability of the four target volatiles ranged from 20% to 45%. The average narrow‐sense heritability of all 13 analyzed floral volatiles was 18% based on parent–offspring regressions. There were pleiotropic effects of the selected floral volatile compounds on other constituents of the floral scent bouquet, on flowering time and on some morphological traits. We found that the whole floral scent bouquet changed, even when there was selection only on single compounds, with the overall phenotypic covariance being unaffected.

Our study demonstrates that floral scent can evolve rapidly under phenotypic selection, but with additional correlated responses in traits that are not direct targets of selection.
Gómez–López‐Hernández Syndrome: A Rare Cause of Bilateral Nonscarring Alopecia
Authors: Saricam Merve Hatun , Tekin Burak , Unver Olcay , Ekinci Gazanfer , Ergun Tulin
Published: September 2015

Gómez–López‐Hernández syndrome is a rare neurocutaneous disorder characterized by the triad of rhombencephalosynapsis, parietal alopecia, and trigeminal anesthesia. We report a 16‐year‐old girl with bilateral parietotemporal alopecia in whom cranial magnetic resonance imaging revealed rhombencephalosynapsis, suggesting a diagnosis of Gómez–López‐Hernández syndrome. Neurologic examination and neuroimaging may be warranted in select patients with parietal alopecia to exclude this uncommon entity.
Melatonin Supplementation During In Vitro Maturation and Development Supports the Development of Porcine Embryos
Authors: Do LTK , Shibata Y , Taniguchi M , Nii M , Nguyen TV , Tanihara F , Takagi M , Otoi T
Published: September 2015

Contents

Melatonin has been reported to improve the in vitro development of embryos in some species. This study was conducted to investigate the effect of melatonin supplementation during in vitro maturation (IVM) and development culture on the development and quality of porcine embryos. In the first experiment, when the in vitro fertilized embryos were cultured with different concentrations of melatonin (0, 10, 25 and 50 ng/ml) for 8 days, the blastocyst formation rate of embryos cultured with 25 ng/ml melatonin (10.7%) was significantly increased (p < 0.05) compared to the control embryos cultured without melatonin (4.2%). The proportion of DNA‐fragmented nuclei in blastocysts derived from embryos cultured with 50 ng/ml melatonin was significantly lower (p < 0.05) than that of embryos cultured without melatonin (2.1% vs 7.2%). In the second experiment, when oocytes were cultured in the maturation medium supplemented with different concentrations of melatonin (0, 10, 25 and 50 ng/ml), fertilized and then cultured with 25 ng/ml melatonin for 8 days, there were no significant differences in the rates of cleavage and blastocyst formation among the groups. However, the proportions (2.7–5.4%) of DNA‐fragmented nuclei in blastocysts derived from oocytes matured with melatonin were significantly decreased (p < 0.05) compared to those (8.9%) from oocytes matured without melatonin, irrespective of the concentration of melatonin. Our results suggest that supplementation of the culture media with melatonin (25 ng/ml) during IVM and development has beneficial effects on the developmental competence and quality of porcine embryos.
Association between asthma and body mass index and socioeconomic status: A cross‐sectional study on 849 659 adolescents
Authors: Gordon Barak , Hassid Aviad , Bar‐Shai Amir , Derazne Estela , Tzur Dorit , Hershkovich Oded , Afek Arnon
Published: September 2015

Background and objective

Asthma is associated with body mass index (BMI), but its association with socioeconomic status (SES) is controversial. The combined effect of SES and BMI on asthma prevalence is undetermined.

Methods

Seventeen‐year‐old pre‐recruits to the Israeli Defense Forces underwent routine physical examinations. SES was determined according to established criteria based on place of residence. The study population was divided according to classic weight groups and three SES groups (low, medium and high). Univariable and multivariable logistic regression models were applied to assess odds ratios (OR) of BMI and SES groups for asthma prevalence. The combined effect of BMI and SES was also calculated.

Results

The 849 659 subjects included 480 993 males (9.5% asthma prevalence) and 368 666 females (6.7% asthma prevalence). Increased BMI were associated with increased OR for asthma in females (1.44, 95% CI 1.36–1.52 for obese vs normal weight). Males had a J‐shaped curve (OR 1.24 95% CI 1.2–1.29 for obese, 1.12, 95% CI 1.08–1.16 for underweight, both vs normal weight). OR adjusted to SES did not change significantly. All SES groups produced a linear curve (1.59 95% CI 1.53–1.66 for females and 1.79 95% CI 1.74–1.84 for males). Adjustment of SES to BMI produced no significant change in OR. When all groups were compared with the normal weight/lower SES group, the highest OR was for the obese/higher SES group (2.32 95% CI 2.05–2.64 for females and 1.99 95% CI 1.83–2.13 for males).

Conclusions

Both BMI and SES are co‐independently associated with asthma in adolescent males and females
How microRNAs orchestrate the lung's biological responses
Authors: Yang Ian A. , Vaughan Annalicia
Published: September 2015

See article, page 1206
Modelling Heatwaves in Central France: A Case-Study in Extremal Dependence
Authors: Winter Hugo C. , Tawn Jonathan A.
Published: September 2015

Heatwaves are phenomena that have large social and economic consequences. Understanding and estimating the frequency of such events are of great importance to climate scientists and decision makers. Heatwaves are a type of extreme event which are by definition rare and as such there are few data in the historical record to help planners. Extreme value theory is a general framework from which inference can be drawn from extreme events. When modelling heatwaves it is important to take into account the intensity and duration of events above a critical level as well as the interaction between both factors. Most previous methods assume that the duration distribution is independent of the critical level that is used to define a heatwave: a shortcoming that can lead to incorrect inferences. The paper characterizes a novel method for analysing the temporal dependence of heatwaves with reference to observed temperatures from Orleans in central France. This method enables estimation of the probabilities for heatwave events irrespectively of whether the duration distribution is independent of the critical level. The methods are demonstrated by estimating the probability of an event more severe than the 2003 European heatwave or an event that causes a specified increase in mortality.
Comparing Two Binary Diagnostic Tests with Repeated Measurements
Authors: Steiner Stefan H. , Danila Oana , Cotton Cecilia A. , Severn Daniel , Mackay R. Jock
Published: September 2015

We compare two binary diagnostic tests when each subject is measured more than once with each test and with a gold standard. We introduce a new model that allows the correlation between two measurements on a single subject by the same test to be different from the correlation between two measurements by different tests. We show that moment estimators of the population parameters for the mean sensitivities and specificities are virtually identical to the maximum likelihood estimates from our random-effects model. We apply the model to data comparing two rapid malaria tests and provide guidance for choosing the number of subjects and repeated measurements.
A limit to the divergent allele advantage model supported by variable pathogen recognition across HLA‐DRB1 allele lineages
Authors: Lau Q. , Yasukochi Y. , Satta Y.
Published: September 2015

Genetic diversity in human leukocyte antigen (HLA) molecules is thought to have arisen from the co‐evolution between host and pathogen and maintained by balancing selection. Heterozygote advantage is a common proposed scenario for maintaining high levels of diversity in HLA genes, and extending from this, the divergent allele advantage (DAA) model suggests that individuals with more divergent HLA alleles bind and recognize a wider array of antigens. While the DAA model seems biologically suitable for driving HLA diversity, there is likely an upper threshold to the amount of sequence divergence. We used peptide‐binding and pathogen‐recognition capacity of DRB1 alleles as a model to further explore the DAA model; within the DRB1 locus, we examined binding predictions based on two distinct phylogenetic groups (denoted group A and B) previously identified based on non‐peptide‐binding region (PBR) nucleotide sequences. Predictions in this study support that group A allele and group B allele lineages have contrasting binding/recognition capacity, with only the latter supporting the DAA model. Furthermore, computer simulations revealed an inconsistency in the DAA model alone with observed extent of polymorphisms, supporting that the DAA model could only work effectively in combination with other mechanisms. Overall, we support that the mechanisms driving HLA diversity are non‐exclusive. By investigating the relationships among HLA alleles, and pathogens recognized, we can provide further insights into the mechanisms on how humans have adapted to infectious diseases over time.
Immunology in Africa
Authors: Cose Stephen , Bagaya Bernard , Nerima Barbara , Joloba Moses , Kambugu Andrew , Tweyongyere Robert , Dunne David W. , Mbidde Edward , Kaleebu Pontiano , Elliott Alison M.
Published: September 2015

Africa is a continent with a large burden of both infectious and non‐communicable diseases. If we are to move forward as a continent, we need to equip our growing cadre of exceptional young scientists with the skills needed to tackle the diseases endemic to this continent. For this, immunology is among the key disciplines. Africans should be empowered to study and understand the diseases that affect them, and to perform their cutting‐edge research in their country of origin. This requires a multifaceted approach, with buy‐in from funders, overseas partners and perhaps, most important of all, African governments themselves.
CORRELATIONS AMONG ULTRASONOGRAPHIC MEASUREMENTS OF OPTIC NERVE SHEATH DIAMETER, AGE, AND BODY WEIGHT IN CLINICALLY NORMAL HORSES
Authors: Cooley Stacy D. , Scrivani Peter V. , Thompson Margret S. , Irby Nita L. , Divers Thomas J. , Erb Hollis N.
Published: September 2015

Early diagnosis of high intracranial pressure (ICP) is critical for minimizing progressive brain injury due to reduced cerebral perfusion. In people, detecting enlargement of the optic nerve sheath diameter (ONSD) by transpalpebral ultrasonography has been found to be an accurate test for high ICP. Aims of this prospective, observational, cross‐sectional study were to test hypotheses that (1) ultrasonographic measurement of ONSD would be repeatable in horses, (2) have acceptable interobserver agreement, and (3) would be correlated with age and body weight. The sample population included 48 horses without clinical signs of high ICP and with varying ages and body weights. Two observers independently performed ONSD measurements in both eyes. All measurements ranged from 2.6 to 6.5 mm. The mean difference of repeated measures within observers was ≤0.1 mm and the coefficients of variation ranged from 5.0% to 8.8%. The mean difference of measures between observers was ≤0.2 mm. After correcting for performing multiple tests, no significant rank correlation (all r < 0.4 [absolute value]) was detected between ONSD and age or body weight. However, we observed smaller ONSD in foals versus adults (all P ≤ 0.002). In the foals, all observed measures of rostrocaudal and dorsoventral ONSD were <5 mm. In the adults, all observed measures of rostrocaudal and dorsoventral ONSD were ≤6.5 mm. Findings indicated that ultrasonographic ONSD measurement is a feasible test for use in horses of varying ages and sizes. Further investigation of this ultrasonographic measure as a clinical test for horse with suspected high ICP is warranted.
Topological K-theory of complex noncommutative spaces
Authors: Blanc Anthony
Published: September 2015

The purpose of this work is to give a definition of a topological K-theory for dg-categories over$\mathbb{C}$and to prove that the Chern character map from algebraic K-theory to periodic cyclic homology descends naturally to this new invariant. This topological Chern map provides a natural candidate for the existence of a rational structure on the periodic cyclic homology of a smooth proper dg-algebra, within the theory of noncommutative Hodge structures. The definition of topological K-theory consists in two steps: taking the topological realization of algebraic K-theory and inverting the Bott element. The topological realization is the left Kan extension of the functor ‘space of complex points’ to all simplicial presheaves over complex algebraic varieties. Our first main result states that the topological K-theory of the unit dg-category is the spectrum$\mathbf{BU}$. For this we are led to prove a homotopical generalization of Deligne’s cohomological proper descent, using Lurie’s proper descent. The fact that the Chern character descends to topological K-theory is established by using Kassel’s Künneth formula for periodic cyclic homology and the proper descent. In the case of a dg-category of perfect complexes on a separated scheme of finite type, we show that we recover the usual topological K-theory of complex points. We show as well that the Chern map tensorized with$\mathbb{C}$is an equivalence in the case of a finite-dimensional associative algebra – providing a formula for the periodic homology groups in terms of the stack of finite-dimensional modules.
Skeletal muscle hypoxia‐inducible factor‐1 and exercise
Authors: Lindholm Malene E. , Rundqvist Helene
Published: September 2015

New Findings

What is the topic of this review?

The role of hypoxia and, more specifically, the role of the hypoxia‐sensitive transcription factor hypoxia‐inducible factor‐1 (HIF‐1) in skeletal muscle adaptation to exercise.

What advances does it highlight?

Skeletal muscle HIF‐1 induces genes involved in angiogenesis and glycolysis. It may also contribute to an active inhibition of oxygen consumption and aerobic metabolism, features discordant with exercise adaptation. Although acute exercise has been shown to activate HIF‐1 in skeletal muscle, this activation may be blunted after a period of endurance exercise training, possibly through increased expression of the negative regulators of HIF.

Reduced oxygen levels in skeletal muscle during exercise are a consequence of increased oxygen consumption. The cellular response to hypoxia is conferred to a large extent by activation of the hypoxia‐sensitive transcription factor hypoxia‐inducible factor‐1 (HIF‐1). The target genes of HIF‐1 increase oxygen transport through mechanisms such as erythropoietin‐mediated erythropoiesis and vascular endothelial growth factor‐induced angiogenesis and improve tissue function during low oxygen availability through increased expression of glucose transporters and glycolytic enzymes, which makes HIF‐1 an interesting candidate as a mediator of skeletal muscle adaptation to endurance training. However, HIF‐1 may also inhibit cellular oxygen consumption and mitochondrial oxidative metabolism, features discordant with the phenotype of a trained muscle. Skeletal muscle readily adjusts to altered functional demands. Adaptation of skeletal muscle to long‐term aerobic training enables better aerobic performance at higher intensities through improved metabolic capacity and oxygen supply. The components of acute exercise that act as triggers for adaptation are still largely unknown; however, an early hypothesis was that local hypoxia acts as a possible stimulus for exercise adaptation. The hypoxia‐sensitive subunit, HIF‐1α, is stabilized in skeletal muscle in response to an acute bout of endurance exercise. However, long‐term endurance exercise seems to attenuate the acute HIF‐1α response. This attenuation is concurrent with an increase in expression of several negative regulators of the HIF system. We propose that the HIF‐1α response is blunted in response to long‐term exercise training through induction of its negative regulators and that this inhibition enables the enhanced oxidative metabolism that is part of a local physiological response to exercise.
Measurement of gold nanofilm dose enhancement using unlaminated radiochromic film
Authors: Rakowski Joseph T. , Laha Suvra S. , Snyder Michael G. , Buczek Matthew G. , Tucker Mark A. , Liu Fangchao , Mao Guangzhao , Hillman Yair , Lawes Gavin
Published: September 2015

Purpose:

Bombarding high‐Z material with x‐ray radiation releases Auger electrons and Coster–Kronig electrons, along with deeper penetrating fluorescent x‐rays and photoelectrons. The Auger and Coster–Kronig electron penetration distance is on the order of nanometers to micrometers in water or tissue, creating a large dose enhancement accompanied by a RBE greater than 1 at the cellular level. The authors’ aim is to measure the gold nanofilm dose enhancement factor (DEF) at the cellular level with unlaminated radiochromic film via primary 50 kVp tungsten x‐ray spectrum interaction, similar to an electronic brachytherapy spectrum.

Methods:

Unlaminated Gafchromic® EBT2 film and Monte Carlo modeling were combined to derive DEF models. Gold film of thickness 23.1 ±  4.3 nm and surface roughness of 1.2 ± 0.2 nm was placed in contact with unlaminated radiochromic film in a downstream orientation and exposed to a 50 kVp tungsten bremsstrahlung, mean energy 19.2 keV. Film response correction factors were derived by Monte Carlo modeling of electron energy deposition in the film's active layer, and by measuring film energy dependence from 4.5 keV to 50 kVp.

Results:

The measured DEF within a 13.6 μm thick water layer was 0.29 with a mean dose of 94 ± 9.4 cGy from Au emissions and 324 ± 32.4 cGy from the 50 kVp primary beam. Monte Carlo derived correction factors allowed determination of Au contributed dose in shallower depths at 0.25 μm intervals. Maximum DEF of 18.31 was found in the first 0.25 μm water depth.

Conclusions:

Dose enhancement from Au nanofilm can be measured at the cellular level using unlaminated radiochromic film. Complementing the measured dose value with Monte Carlo calculations allows estimation of dose enhancement at depth increments within the cellular range.
Science Signaling
Podcast for 22 September 2015: SOCS3 prevents pathological retinal neovascularization
Authors: Smith Lois E. H. , Sun Ye , VanHook Annalisa M.
Published: September 2015

SOCS3 activity in neural and glial cells of the retina prevents pathological retinal neovascularization.
Finding a missing link in blood pressure regulation
Authors: Prabakaran Sudhakaran
Published: September 2015

The protease PCSK6 cleaves the zymogen form of the protease corin, which is responsible for cleavage-mediated activation of the hormone atrial natriuretic peptide.
Plants kill pathogens with cyanide
Authors: VanHook Annalisa M.
Published: September 2015

Infection triggers the synthesis of cyanogenic compounds in
Arabidopsis
.
Circulating signals of drug resistance
Authors: Kiberstis Paula A.
Published: September 2015

Analysis of circulating tumor cells from prostate cancer patients reveals a mechanism that contributes to treatment failure.
Small peptide regulates protein activity
Authors: Purnell Beverly A.
Published: September 2015

A small open reading frame encodes peptides that control a ubiquitin ligase for proteasomal processing of a transcription factor.
Efficacy of Posaconazole in a Murine Model of Systemic Infection by Saprochaete capitata
Authors: Thomson Pamela , Guarro Josep , Mayayo Emilio , Capilla Javier
Published: September 2015

The fungus
Saprochaete capitata
causes opportunistic human infections, mainly in immunocompromised patients with hematological malignancies. The best therapy for this severe infection is still unknown. We evaluated the
in vitro
killing activity and the
in vivo
efficacy of posaconazole at 5, 10, or 20 mg/kg twice a day (BID) in a murine neutropenic model of systemic infection with
S. capitata
by testing a set of six clinical isolates. Posaconazole showed fungistatic activity against all of the isolates tested. The different doses of the drug, especially the highest one, showed good efficacy, measured by prolonged survival, reduction of (1-3)-β-
d
-glucan levels in serum, tissue burden reduction, and histopathology.
Cellular Uptake and Localization of Polymyxins in Renal Tubular Cells Using Rationally Designed Fluorescent Probes
Authors: Yun Bo , Azad Mohammad A. K. , Nowell Cameron J. , Nation Roger L. , Thompson Philip E. , Roberts Kade D. , Velkov Tony , Li Jian
Published: September 2015

Polymyxins are cyclic lipopeptide antibiotics that serve as a last line of defense against Gram-negative bacterial superbugs. However, the extensive accumulation of polymyxins in renal tubular cells can lead to nephrotoxicity, which is the major dose-limiting factor in clinical use. In order to gain further insights into the mechanism of polymyxin-induced nephrotoxicity, we have rationally designed novel fluorescent polymyxin probes to examine the localization of polymyxins in rat renal tubular (NRK-52E) cells. Our design strategy focused on incorporating a dansyl fluorophore at the hydrophobic centers of the polymyxin core structure. To this end, four novel regioselectively labeled monodansylated polymyxin B probes (MIPS-9541, MIPS-9542, MIPS-9543, and MIPS-9544) were designed, synthesized, and screened for their antimicrobial activities and apoptotic effects against rat kidney proximal tubular cells. On the basis of the assessment of antimicrobial activities, cellular uptake, and apoptotic effects on renal tubular cells, incorporation of a dansyl fluorophore at either position 6 or 7 (MIPS-9543 and MIPS-9544, respectively) of the polymyxin core structure appears to be an appropriate strategy for generating representative fluorescent polymyxin probes to be utilized in intracellular imaging and mechanistic studies. Furthermore, confocal imaging experiments utilizing these probes showed evidence of partial colocalization of the polymyxins with both the endoplasmic reticulum and mitochondria in rat renal tubular cells. Our results highlight the value of these new fluorescent polymyxin probes and provide further insights into the mechanism of polymyxin-induced nephrotoxicity.
The Nucleoside Analog BMS-986001 Shows GreaterIn VitroActivity against HIV-2 than against HIV-1
Authors: Smith Robert A. , Raugi Dana N. , Wu Vincent H. , Leong Sally S. , Parker Kate M. , Oakes Mariah K. , Sow Papa Salif , Ba Selly , Seydi Moussa , Gottlieb Geoffrey S.
Published: September 2015

Treatment options for individuals infected with human immunodeficiency virus type 2 (HIV-2) are restricted by the intrinsic resistance of the virus to nonnucleoside reverse transcriptase inhibitors (NNRTIs) and the reduced susceptibility of HIV-2 to several protease inhibitors (PIs) used in antiretroviral therapy (ART). In an effort to identify new antiretrovirals for HIV-2 treatment, we evaluated thein vitroactivity of the investigational nucleoside analog BMS-986001 (2′,3′-didehydro-3′-deoxy-4′-ethynylthymidine; also known as censavudine, festinavir, OBP-601, 4′-ethynyl stavudine, or 4′-ethynyl-d4T). In single-cycle assays, BMS-986001 inhibited HIV-2 isolates from treatment-naive individuals, with 50% effective concentrations (EC50s) ranging from 30 to 81 nM. In contrast, EC50s for group M and O isolates of HIV-1 ranged from 450 to 890 nM. Across all isolates tested, the average EC50for HIV-2 was 9.5-fold lower than that for HIV-1 (64 ± 18 nM versus 610 ± 200 nM, respectively; mean ± standard deviation). BMS-986001 also exhibited full activity against HIV-2 variants whose genomes encoded the single amino acid changes K65R and Q151M in reverse transcriptase, whereas the M184V mutant was 15-fold more resistant to the drug than the parental HIV-2ROD9strain. Taken together, our findings show that BMS-986001 is an effective inhibitor of HIV-2 replication. To our knowledge, BMS-986001 is the first nucleoside analog that, when tested against a diverse collection of HIV-1 and HIV-2 isolates, exhibits more potent activity against HIV-2 than against HIV-1 in culture.
Efficacy of Single and Combined Antibiotic Treatments of Anthrax in Rabbits
Authors: Weiss Shay , Altboum Zeev , Glinert Itai , Schlomovitz Josef , Sittner Assa , Bar-David Elad , Kobiler David , Levy Haim
Published: September 2015

Respiratory anthrax is a fatal disease in the absence of early treatment with antibiotics. Rabbits are highly susceptible to infection with
Bacillus anthracis
spores by intranasal instillation, succumbing within 2 to 4 days postinfection. This study aims to test the efficiency of antibiotic therapy to treat systemic anthrax in this relevant animal model. Delaying the initiation of antibiotic administration to more than 24 h postinfection resulted in animals with systemic anthrax in various degrees of bacteremia and toxemia. As the onset of symptoms in humans was reported to start on days 1 to 7 postexposure, delaying the initiation of treatment by 24 to 48 h (time frame for mass distribution of antibiotics) may result in sick populations. We evaluated the efficacy of antibiotic administration as a function of bacteremia levels at the time of treatment initiation. Here we compare the efficacy of treatment with clarithromycin, amoxicillin-clavulanic acid (Augmentin), imipenem, vancomycin, rifampin, and linezolid to the previously reported efficacy of doxycycline and ciprofloxacin. We demonstrate that treatment with amoxicillin-clavulanic acid, imipenem, vancomycin, and linezolid were as effective as doxycycline and ciprofloxacin, curing rabbits exhibiting bacteremia levels of up to 10
5
CFU/ml. Clarithromycin and rifampin were shown to be effective only as a postexposure prophylactic treatment but failed to treat the systemic (bacteremic) phase of anthrax. Furthermore, we evaluate the contribution of combined treatment of clindamycin and ciprofloxacin, which demonstrated improvement in efficacy compared to ciprofloxacin alone.
In Vitro
Activity of Simeprevir against Hepatitis C Virus Genotype 1 Clinical Isolates and Its Correlation with NS3 Sequence and Site-Directed Mutants
Authors: Verbinnen Thierry , Fevery Bart , Vijgen Leen , Jacobs Tom , De Meyer Sandra , Lenz Oliver
Published: September 2015

Simeprevir (TMC435) is a once-daily, single-pill, oral hepatitis C virus (HCV) NS3 protease inhibitor approved for the treatment of chronic HCV infection. Phenotypic characterization of baseline isolates and isolates from HCV genotype 1-infected patients failing with a simeprevir-based regimen was performed using chimeric replicons carrying patient-derived NS3 protease sequences. Cutoff values differentiating between full susceptibility to simeprevir (≤2.0-fold reduction in simeprevir activity) and low-level versus high-level resistance (≥50-fold reduction in simeprevir activity) were determined. The median simeprevir fold change in the 50% effective concentration (FC) of pretreatment genotype 1a isolates, with and without Q80K, and genotype 1b isolates was 11, 0.9, and 0.4, respectively. Naturally occurring NS3 polymorphisms that reduced simeprevir activity, other than Q80K, were uncommon in the simeprevir studies and generally conferred low-level resistance
in vitro
. Although the proportion of patients with failure differed by HCV geno/subtype and/or presence of baseline Q80K, the level of simeprevir resistance observed at failure was similarly high irrespective of type of failure, HCV genotype 1 subtype, and presence or absence of baseline Q80K. At the end of the study, simeprevir activity against isolates that lost the emerging amino acid substitution returned to pretreatment values. Activity of simeprevir against clinical isolates and site-directed mutant replicons harboring the corresponding single or double amino acid substitutions correlated well, showing that simeprevir resistance can be attributed to these substitutions. In conclusion, pretreatment NS3 isolates were generally fully susceptible (FC, ≤2.0) or conferred low-level resistance to simeprevir
in vitro
(FC, >2.0 and <50). Treatment failure with a simeprevir-based regimen was associated with emergence of high-level-resistance variants (FC, ≥50).
Effect of Preexposure to Triazoles on Susceptibility and Virulence of Rhizopus oryzae
Authors: Bellanger Anne-Pauline , Albert Nathaniel D. , Lewis Russell E. , Walsh Thomas J. , Kontoyiannis Dimitrios P.
Published: September 2015

Triazole prophylaxis has become the norm in patients with hematological malignancies. Breakthrough infections caused by
Mucorales
during triazole prophylaxis remain a challenging problem. We found that preexposure of
Rhizopus oryzae
to antifungal triazoles (fluconazole, voriconazole, posaconazole, and itraconazole) did not modify the
in vitro
susceptibility of
Rhizopus oryzae
to posaconazole. In contrast, preexposure of
Rhizopus
to triazoles was associated with the enhanced
in vitro
susceptibility of
R. oryzae
to amphotericin B. Preexposure to posaconazole did not alter the virulence of
R. oryzae
in the fly model of mucormycosis.
Impact of Glycopeptide Resistance in Staphylococcus aureus on the Dalbavancin
In Vivo
Pharmacodynamic Target
Authors: Lepak A. , Marchillo K. , VanHecker J. , Andes D.
Published: September 2015

Dalbavancin is a novel lipoglycopeptide with activity against
Staphylococcus aureus
, including glycopeptide-resistant isolates. The
in vivo
investigation reported here tested the effects of this antibiotic against seven
S. aureus
isolates with higher MICs, including several vancomycin-intermediate strains. Results of 1-log kill and 2-log kill were achieved against seven and six of the isolates, respectively. The mean free-drug area under the concentration-time curve (
f
AUC)/MIC values for net stasis, 1-log kill, and 2-log kill were 27.1, 53.3, and 111.1, respectively.
In Vitro
and Molecular Surveillance for Antimalarial Drug Resistance in Plasmodium falciparum Parasites in Western Kenya Reveals Sustained Artemisinin Sensitivity and Increased Chloroquine Sensitivity
Authors: Lucchi Naomi W. , Komino Franklin , Okoth Sheila Akinyi , Goldman Ira , Onyona Philip , Wiegand Ryan E. , Juma Elizabeth , Shi Ya Ping , Barnwell John W. , Udhayakumar Venkatachalam , Kariuki Simon
Published: September 2015

Malaria control is hindered by the evolution and spread of resistance to antimalarials, necessitating multiple changes to drug policies over time. A comprehensive antimalarial drug resistance surveillance program is vital for detecting the potential emergence of resistance to antimalarials, including current artemisinin-based combination therapies. An antimalarial drug resistance surveillance study involving 203
Plasmodium falciparum
malaria-positive children was conducted in western Kenya between 2010 and 2013. Specimens from enrolled children were analyzed
in vitro
for sensitivity to chloroquine (CQ), amodiaquine (AQ), mefloquine (MQ), lumefantrine, and artemisinin derivatives (artesunate and dihydroartemisinin) and for drug resistance allele polymorphisms in
P. falciparum crt
(
Pfcrt
),
Pfmdr-1
, and the K13 propeller domain (K13). We observed a significant increase in the proportion of samples with the
Pfcrt
wild-type (CVMNK) genotype, from 61.2% in 2010 to 93.0% in 2013 (
P
< 0.0001), and higher proportions of parasites with elevated sensitivity to CQ
in vitro
. The majority of isolates harbored the wild-type N allele in
Pfmdr-1
codon 86 (93.5%), with only 7 (3.50%) samples with the N86
Y
mutant allele (the mutant nucleotide is underlined). Likewise, most isolates harbored the wild-type
Pfmdr-1
D1246 allele (79.8%), with only 12 (6.38%) specimens with the D1246
Y
mutant allele and 26 (13.8%) with mixed alleles. All the samples had a single copy of the
Pfmdr-1
gene (mean of 0.907 ± 0.141 copies). None of the sequenced parasites had mutations in K13. Our results suggest that artemisinin is likely to remain highly efficacious and that CQ sensitivity appears to be on the rise in western Kenya.