bluuebunny/crossref_metadata_2025 huggingface dataset:
Saprochaete capitata as an emerging fungus among patients with haematological malignencies
Authors: Ulu‐Kilic Aysegul , Atalay Mustafa Altay , Metan Gökhan , Cevahir Fatma , Koç Nedret , Eser Bülent , Çetin Mustafa , Kaynar Leyla , Alp Emine
Published: July 2015

Saprochaete capitata is a very rare pathogen that causes invasive disease particularly in patients with haematological malignancies. We recognised a clustering of S. capitata fungaemia in recent years. So, we report our 6‐year surveillance study of fungaemia among patients with haematological malignancies and haematopoietic stem cell transplant. We performed a retrospective and observational study. Hospitalised patients aged >18 years with haematological malignancies were included in the study. A total of 51 fungaemia episodes of 47 patients were analysed. The characteristics of fungaemia in patients with S. capitata compared to patients with candidemia. Median duration of neutropenia was 21.5 days in patients with S. capitata fungaemia, whereas this duration was significantly shorter in patients with candidemia (8 days). Interval between first and last positive culture was significantly longer in patients with S. capitata fungaemia (P < 0.05). Previous use of caspofungin was significantly more common in patients with S. capitata fungaemia. Thirty‐day mortality was found 40% for patients with candidemia, whereas it was 39% for patients with S. capitata. In conclusion, despite its limitations this study showed that a novel and more resistant yeast‐like pathogen become prevalent due to use of caspofungin in patients with long‐lasting neutropenia which was the most noteworthy finding of this 6‐year surveillance study.
A roadmap for research on crassulacean acid metabolism (CAM) to enhance sustainable food and bioenergy production in a hotter, drier world
Authors: Yang Xiaohan , Cushman John C. , Borland Anne M. , Edwards Erika J. , Wullschleger Stan D. , Tuskan Gerald A. , Owen Nick A. , Griffiths Howard , Smith J. Andrew C. , De Paoli Henrique C. , Weston David J. , Cottingham Robert , Hartwell James , Davis Sarah C. , Silvera Katia , Ming Ray , Schlauch Karen , Abraham Paul , Stewart J. Ryan , Guo Hao‐Bo , Albion Rebecca , Ha Jungmin , Lim Sung Don , Wone Bernard W. M. , Yim Won Cheol , Garcia Travis , Mayer Jesse A. , Petereit Juli , Nair Sujithkumar S. , Casey Erin , Hettich Robert L. , Ceusters Johan , Ranjan Priya , Palla Kaitlin J. , Yin Hengfu , Reyes‐García Casandra , Andrade José Luis , Freschi Luciano , Beltrán Juan D. , Dever Louisa V. , Boxall Susanna F. , Waller Jade , Davies Jack , Bupphada Phaitun , Kadu Nirja , Winter Klaus , Sage Rowan F. , Aguilar Cristobal N. , Schmutz Jeremy , Jenkins Jerry , Holtum Joseph A. M.
Published: July 2015

Crassulacean acid metabolism (CAM) is a specialized mode of photosynthesis that features nocturnal CO2 uptake, facilitates increased water‐use efficiency (WUE), and enables CAM plants to inhabit water‐limited environments such as semi‐arid deserts or seasonally dry forests. Human population growth and global climate change now present challenges for agricultural production systems to increase food, feed, forage, fiber, and fuel production. One approach to meet these challenges is to increase reliance on CAM crops, such as Agave and Opuntia, for biomass production on semi‐arid, abandoned, marginal, or degraded agricultural lands. Major research efforts are now underway to assess the productivity of CAM crop species and to harness the WUE of CAM by engineering this pathway into existing food, feed, and bioenergy crops. An improved understanding of CAM has potential for high returns on research investment. To exploit the potential of CAM crops and CAM bioengineering, it will be necessary to elucidate the evolution, genomic features, and regulatory mechanisms of CAM. Field trials and predictive models will be required to assess the productivity of CAM crops, while new synthetic biology approaches need to be developed for CAM engineering. Infrastructure will be needed for CAM model systems, field trials, mutant collections, and data management.
Rectal puncture complicating caudal blockade in a child with severe rectal distension
Authors: Sathianathan Vivian , Dobby Nadine
Published: July 2015

We describe a case of unrecognized rectal puncture following unsuccessful caudal blockade in a patient later found to have marked rectal distension on MRI. This may have contributed to the rectal injury.
Respiratory syncytial virus infections in pediatric transplant recipients: A Canadian Paediatric Surveillance Program study
Authors: Robinson Joan L. , Grenier Danielle , MacLusky Ian , Allen Upton D.
Published: July 2015

The incidence and spectrum of severity of RSV infections in SOT or HSCT recipients is not known. From September 2010 through August 2013, pediatricians were surveyed monthly by the CPSP for SOT or HSCT recipients with RSV infection within two yr post‐transplant. There were 24 completed case report forms that fit the inclusion criteria (10 HSCT and 14 SOT recipients). Six of 24 cases (25%) remained outpatients, and 11 (46%) were managed on an inpatient ward, while seven (29%) required intensive care of which five required mechanical ventilation and two died of RSV infection. Ten of 23 cases (43%) were nosocomial with these data not recorded for one case. Many transplant recipients recover uneventfully from RSV infection in the first two yr post‐transplant. However, severe disease and death also occur. Larger studies are required to establish risk factors for poor outcomes. Prevention of nosocomial RSV should be a priority in transplant recipients.
Second‐Order Logic and Set Theory
Authors: Väänänen Jouko
Published: July 2015

Both second‐order logic and set theory can be used as a foundation for mathematics, that is, as a formal language in which propositions of mathematics can be expressed and proved. We take it upon ourselves in this paper to compare the two approaches, second‐order logic on one hand and set theory on the other hand, evaluating their merits and weaknesses. We argue that we should think of first‐order set theory as a very high‐order logic.
Divine Ineffability
Authors: Bennett‐Hunter Guy
Published: July 2015

Though largely neglected by philosophers, the concept of ineffability is integral to the Christian mystical tradition, and has been part of almost every philosophical discussion of religious experience since the early twentieth century. After a brief introduction, this article surveys the most important discussions of divine ineffability, observing that the literature presents two mutually reinforcing obstacles to a coherent account of the concept, creating the impression that philosophical reflection on the subject had reached an impasse. The article goes on to survey some more recent work, which draws on the conceptual resources of existential phenomenology, pragmatism, and the later Wittgenstein. It shows that this work has made possible a new philosophical account of divine ineffability that surmounts the obstacles, overcomes the impasse and makes divine ineffability, once again, a live option in philosophy of religion. The article concludes with some brief remarks on how this alternative approach reflects recent trends in the discipline as a whole and has the potential to make a valuable contribution to live research questions in epistemology of religion.
Apomixis does not affect visitation to flowers of Melastomataceae, but pollen sterility does
Authors: Maia F. R. , Varassin I. G. , Goldenberg R.
Published: July 2015

Apomixis is an asexual seed reproduction mechanism thorough which embryos are originated from material tissues inside the ovules, without precedent fertilisation. It allows plants to colonise new habitats, even in places where flower visitors are scarce or where plants are isolate. Apomixis seems to be related to pollen sterility and, in species with flowers that offer pollen as a reward for pollinators, the amount or quality of the pollen offered by these species may influence the amount of the visits and specific composition of the visitors. In order to test this hypothesis, we studied breeding systems of 16 species of Melastomataceae and their flower visitors, evaluating composition and abundance of the visits to apomictic and sexual species. Apomictic plants with no viable pollen or with pollen with low viability did not receive visits from pollinators, and consequently probably produce strictly apomictic fruits. On the other hand, apomictic and sexual plants with high pollen viability do receive visits; in this case, apomictic plants may produce fruits and seeds through both sexual and apomictic methods. The species composition of insects visiting Melastomataceae with high pollen viability was similar, regardless of whether the plants were apomictic or not. It seems that pollen viability levels are important to determine visits to the flowers irrespective of breeding system.
Reproductive biology and nectar production of the Mexican endemic Psittacanthus auriculatus (Loranthaceae), a hummingbird‐pollinated mistletoe
Authors: Pérez‐Crespo M. J. , Ornelas J. F. , Martén‐Rodríguez S. , González‐Rodríguez A. , Lara C.
Published: July 2015

Many mistletoe species produce ‘bird’‐pollinated flowers; however, the reproductive biology of the majority of these species has not been studied. Psittacanthus auriculatus is a Mexican endemic mistletoe, most common in open, dry mesquite grassland. Knowledge of the reproductive biology of P. auriculatus is essential for understanding species formation and diversification of Psittacanthus mistletoes, but it is currently poorly understood. Thus, we studied floral biology and phenology, nectar production and breeding system and pollination of this species. The hermaphroditic red‐pink flowers open from the middle to the tip and petals are curly, but remain partially fused forming a floral tube of ca. 20‐mm long. Flowers are partially protandrous, produce large amounts of nectar, last 2 days, and stigma receptivity is highest during the second day. We recorded hummingbirds (Cynanthus latirostris, Hylocharis leucotis, Amazilia beryllina, A. violiceps, Calothorax lucifer, Archilochus colubris) and less commonly butterflies (Agraulis vanillae, Anteos clorinde, Papilio multicaudatus, Phocides urania, Phoebis sennae) as floral visitors. P. auriculatus flowers are self‐compatible. However, this mistletoe is an obligate animal‐pollinated species, as the sensitive stigma avoids self‐pollination. Under natural conditions, reproductive success was higher than in manually selfed or cross‐pollinated flowers, likely due to the traplining foraging behaviour of hummingbirds. We suggest that the apparent efficient foraging behaviour of hummingbirds maintains gene flow among P. auriculatus, promoting outcrossing.
A test of phenotypic selection on petal form in the wild carnation, Dianthus inoxianus
Authors: Herrera J. , Balao F.
Published: July 2015

Floral phenotypes are considered a product of pollinator‐mediated selection, which also has the side effect of decreasing floral variation within species. Correlates of flower visibility and function were studied in a carnation species (Dianthus inoxianus), which has crepuscular anthesis and scent‐based pollination by the hawkmoth Hyles livornica. We also assessed constancy of flower form in nature and in cultivation and, using fruit set as an estimate of plant relative fitness, tested whether the main pollinator exerted phenotypic selection on floral traits. Petal claw, which is roughly equivalent to the average depth at which an insect's proboscis must be inserted to reach nectar, was remarkably constant among wild plants (coefficient of variation 8%). In contrast, the area of the visible part of the petal, and the intensity of a coloured dot pattern on the petal was very variable (respectively CV = 34% and 102%). Cultivation in a common environment revealed significant variation among genotypes as regards petal area, degree of laciniation and extension of the dot pattern, but not petal claw length, which remained steady. Petal area, shape and colour did not affect relative fitness during the year of study, but plants with intermediate petal claws (i.e. floral tubes) set significantly more fruit. Results are compatible with low response of the main pollinator to variation in visual traits (petal area, laciniation, colour) and high responsiveness to variation in other aspects (tube length). Inconsistent phenotypic selection by pollinators may add to other causes of floral variation in the genus Dianthus, the causes of which are discussed.
Sources of Fluctuations in the Real Exchange Rates and Trade Balances of the G‐7: A Sign Restriction VAR Approach
Authors: Huh Hyeon‐seung , Kwon Won Soon
Published: July 2015

This paper estimates structural vector autoregression models of output, the real exchange rate and trade balance for the group of seven leading advanced economies (G‐7). Unlike previous studies, we do not impose long‐run purchasing power parity as an identifying assumption; instead, the shocks underlying the model are structurally identified using a set of theory‐consistent sign restrictions. Empirical results show that nominal shocks account for most of the long‐run variability in trade balances across the G‐7 countries. We are able to attribute this finding to long‐run movements in the real exchange rate, as the real exchange rate is significantly affected by nominal shocks in the long run.
Emotion Socialization in the Context of Risk and Psychopathology: Mother and Father Socialization of Anger and Sadness in Adolescents with Depressive Disorder
Authors: Shortt Joann Wu , Katz Lynn Fainsilber , Allen Nicholas B. , Leve Craig , Davis Betsy , Sheeber Lisa B.
Published: July 2015

This study examined parental emotion socialization processes associated with adolescent unipolar depressive disorder. Adolescent participants (N = 107; 42 boys) were selected either to meet criteria for current unipolar depressive disorder or to be psychologically healthy as defined by no lifetime history of psychopathology or mental health treatment and low levels of current depressive symptomatology. A multi‐source/method measurement strategy was used to assess mothers’ and fathers’ responses to adolescent sad and angry emotion. Each parent and adolescent completed questionnaire measures of parental emotion socialization behavior, and participated in meta‐emotion interviews and parent‐adolescent interactions. As hypothesized, parents of adolescents with depressive disorder engaged in fewer supportive responses and more unsupportive responses overall relative to parents of non‐depressed adolescents. Between group differences were more pronounced for families of boys, and for fathers relative to mothers. The findings indicate that parent emotion socialization is associated with adolescent depression and highlight the importance of including fathers in studies of emotion socialization, especially as it relates to depression.
Do Young Children's Representations of Discipline and Empathy Moderate the Effects of Punishment on Emotion Regulation?
Authors: Lee Young‐Eun , Brophy‐Herb Holly E. , Vallotton Claire D. , Griffore Robert J. , Carlson John S. , Robinson JoAnn L.
Published: July 2015

This study examined whether children's representations of parenting (perceptions of authoritative discipline and empathy) moderated the association between harsh punishment—including corporal punishment (CP) and verbal punishment (VP)—and children's emotion regulation at the age of five years. Participants were 559 low‐income mother‐child dyads. Maternal self‐reports and home observations were used to measure punishment. Children's representations were assessed using the MacArthur Story Stem Battery. Children's emotion regulation was assessed by observer rating via the Leiter International Performance Scale–Revised. Hierarchical multiple regressions revealed that children's authoritative disciplinary representations moderated the effects of both VP and CP on children's emotion regulation. Empathic representations moderated the effects of VP only on children's emotion regulation. The current findings highlight the role of children's internal representations as potential protective factors in the context of harsher forms of punishment.
Phases, Reflexives, and Definiteness
Authors: Despić Miloje
Published: July 2015

This paper investigates a puzzling correlation between two seemingly disparate phenomena: the crosslinguistic distribution of reflexive possessives and definiteness marking. As observed in Reuland 2007, 2011 and supported here by additional crosslinguistic evidence, reflexive possessives are available only in languages that either lack definiteness marking or encode definiteness postnominally. Languages that have prenominal (article‐like) definiteness marking, on the other hand, systematically lack reflexive possessives. I argue that such facts support a particular approach to reflexive binding—specifically, one that has the following properties: (i) binding domains are stated in terms of phases, (ii) in addition toCPs andvPs,DPs are phases, and (iii)DPis not universal. I closely examine another robust crosslinguistic correlation regarding definiteness marking—Bošković's (2008) Left Branch Extraction generalization—and show how it directly follows from the key assumptions of the analysis. I situate my proposals within a broader context of the phase theory, arguing that the syntactic representation of (in)definiteness is the crucial factor in determining the phasehood status of nominal categories. I extend my analysis to the clausal domain and discuss it in the context of languages that allow reflexives in the subject position.
Determinants of Firm Value in Kenya: Case of Commercial Banks Listed at the Nairobi Securities Exchange
Authors: Ayako Aloys , Wamalwa Fidelis
Published: July 2015

This study analysed the determinants of firm value of commercial banks listed at the Nairobi Securities Exchange (NSE). The analysis was based on secondary panel data over the period 2002 to 2012. The estimation results of the random effects regression model showed that, though statistically significant (p<0.05), the joint effects of the determinants under the study was low, accounting for about 30  per cent of the variance of the firm value of the listed commercial banks in Kenya. At the individual determinant level, the estimation results were mixed. While we could not reject the null hypotheses that assets, capital structure, cash flows, dividend ratio and intangible had no statistically significant individual effects on the firm value of the listed commercial banks (p<0.05), we rejected the null hypotheses and concluded that market capitalization had statistically significant individual effects on the firm value of the listed commercial banks (p<0.05). Given the relatively low joint effects of the determinants under the study, we recommends that further studies should be undertaken to identify and include additional firm specific and both industry level and macroeconomic control variables. The studies should also evaluate the effects of alternative computation of firm value on the model estimation results. The studies may focus on firm value of the listed commercial banks and/or other listed firms in the NSE
Fuzzy Multi Objective Linear Programming Problem with Imprecise Aspiration Level and Parameters
Authors: Shahraki Zahra , Allahdadi Mehdi , Mishmast Nehi Hassan
Published: July 2015

This paper considers the multi-objective linear programming problems with fuzzygoal for each of the objective functions and constraints. Most existing works deal withlinear membership functions for fuzzy goals. In this paper, exponential membershipfunction is used.
A research on adaptive control to stabilize and synchronize a hyperchaotic system with uncertain parameters
Authors: Ahmad Israr , Saaban Azizan Bin , Ibrahim Adyda Binti , Al-Hadhrami Said , Shahzad Mohammad , Al-Mahrouqi Sharifa Hilal
Published: July 2015

This paper addresses the chaos control and synchronization problems of a hyperchaotic system. It is assumed that the parameters of the hyperchaotic system are unknown and the system is perturbed by the external disturbance. Based on the Lyapunov stability theory and the adaptive control theory, suitable nonlinear controllers are designed for the asymptotic stability of the closed-loop system both for stabilization of hyperchaos at the origin and complete synchronization of two identical hyperchaotic systems. Accordingly, suitable update laws are proposed to estimate the fully uncertain parameters. All simulation results are carried out to validate the effectiveness of the theoretical findings. The effect of external disturbance is under our discussion.
Effect of hyperinsulinaemia–hyperaminoacidaemia on leg muscle protein synthesis and breakdown: reassessment of the two‐pool arterio‐venous balance model
Authors: Smith Gordon I. , Patterson Bruce W. , Klein Seth J. , Mittendorfer Bettina
Published: July 2015

Key points

Accurate measurements of muscle protein synthesis and breakdown rates are critical for understanding the processes underlying muscle atrophy and hypertrophy.

Several mathematical approaches have been described to derive muscle protein synthesis and breakdown rates from a two‐pool (artery–vein) model including metabolic tracers.

We found that only some of the published approaches provide accurate protein turnover rates and only when the computations are made with mole percent excess as the measure of tracer enrichment and the sum of tracer and tracee as the corresponding concentration in the artery and vein; errors, up to several‐fold in magnitude, result when computations are made with unlabelled concentration only, and/or enrichment expressed as tracer‐to‐tracee ratio or with any of the other equations (irrespective of how concentration and enrichment are expressed).

Interpretation of muscle protein turnover rates and their validity requires careful attention to the mathematical approach used to calculate them.

Accurate measurement of muscle protein turnover is critical for understanding the physiological processes underlying muscle atrophy and hypertrophy. Several mathematical approaches, used in conjunction with a tracer amino acid infusion, have been described to derive protein synthesis and breakdown rates from a two‐pool (artery–vein) model. Despite apparently common underlying principles, these approaches differ significantly (some seem to not take into account arterio‐venous shunting of amino acids, which comprises ∼80–90% of amino acids appearing in the vein) and most do not specify how tracer enrichment (i.e. mole percent excess (MPE) or tracer‐to‐tracee ratio (TTR)) and amino acid concentration (i.e. unlabelled only or total labelled plus unlabelled) should be expressed, which could have a significant impact on the outcome when using stable isotope labelled tracers. We developed equations that avoid these uncertainties and used them to calculate leg phenylalanine (Phe) kinetics in subjects who received a [2H5]Phe tracer infusion during postabsorptive conditions and during a hyperinsulinaemic–euglycaemic clamp with concomitant protein ingestion. These results were compared with those obtained by analysing the same data with previously reported equations. Only some of them computed the results correctly when used with MPE as the enrichment measure and total (tracer+tracee) Phe concentrations; errors up to several‐fold in magnitude were noted when the same approaches were used in conjunction with TTR and/or unlabelled concentration only, or when using the other approaches (irrespective of how concentration and enrichment are expressed). Our newly developed equations should facilitate accurate calculation of protein synthesis and breakdown rates.
Three dimensional dose distribution comparison of simple and complex acquisition trajectories in dedicated breast CT
Authors: Shah Jainil P. , Mann Steve D. , McKinley Randolph L. , Tornai Martin P.
Published: July 2015

Purpose:

A novel breast CT system capable of arbitrary 3D trajectories has been developed to address cone beam sampling insufficiency as well as to image further into the patient's chest wall. The purpose of this study was to characterize any trajectory‐related differences in 3D x‐ray dose distribution in a pendant target when imaged with different orbits.

Methods:

Two acquisition trajectories were evaluated: circular azimuthal (no‐tilt) and sinusoidal (saddle) orbit with ±15° tilts around a pendant breast, using Monte Carlo simulations as well as physical measurements. Simulations were performed with tungsten (W) filtration of a W‐anode source; the simulated source flux was normalized to the measured exposure of a W‐anode source. A water‐filled cylindrical phantom was divided into 1 cm3 voxels, and the cumulative energy deposited was tracked in each voxel. Energy deposited per voxel was converted to dose, yielding the 3D distributed dose volumes. Additionally, three cylindrical phantoms of different diameters (10, 12.5, and 15 cm) and an anthropomorphic breast phantom, initially filled with water (mimicking pure fibroglandular tissue) and then with a 75% methanol‐25% water mixture (mimicking 50–50 fibroglandular‐adipose tissues), were used to simulate the pendant breast geometry and scanned on the physical system. Ionization chamber calibrated radiochromic film was used to determine the dose delivered in a 2D plane through the center of the volume for a fully 3D CT scan using the different orbits.

Results:

Measured experimental results for the same exposure indicated that the mean dose measured throughout the central slice for different diameters ranged from 3.93 to 5.28 mGy, with the lowest average dose measured on the largest cylinder with water mimicking a homogeneously fibroglandular breast. These results align well with the cylinder phantom Monte Carlo studies which also showed a marginal difference in dose delivered by a saddle trajectory in the central slice. Regardless of phantom material or filled fluid density, dose delivered by the saddle scan was negligibly different than the simple circular, no‐tilt scans. The average dose measured in the breast phantom was marginally higher for saddle than the circular no tilt scan at 3.82 and 3.87 mGy, respectively.

Conclusions:

Not only does nontraditional 3D‐trajectory CT scanning yield more complete sampling of the breast volume but also has comparable dose deposition throughout the breast and anterior chest volume, as verified by Monte Carlo simulation and physical measurements.
Technical Note: Automatic real‐time ultrasound tracking of respiratory signal using selective filtering and dynamic template matching
Authors: Wu Jiaze , Li Cheng , Gogna Apoorva , Tan Bien Soo , Ooi London Lucien , Liu Jimin , Yu Haoyong
Published: July 2015

Purpose:

In respiratory motion modeling for liver interventions, the respiratory signal is usually obtained by using special tracking devices to monitor external skin. However, due to intrinsic limits and cost consideration of these tracking devices, a purely ultrasound image‐based approach to tracking the signal is a more feasible option.

Methods:

In this study, a novel image‐based method is proposed to obtain the respiratory signal directly from 2D ultrasound images by automatically identifying and tracking the liver boundary. The boundary identification is a multistage process, which is the key to utilize a Hessian matrix‐based 2D filter to enhance the line‐like liver boundary and weaken other liver tissues. For tracking the identified boundary, a new dynamic template matching technique is first applied to estimate 2D displacements, and a boundary‐specific selection mechanism is then introduced to extract the respiratory signal from the 2D displacements.

Results:

The experiments demonstrate that their method can obtain accurate breathing signals, which are in key phases comparable to the manually annotation and highly consistent to the electromagnetic‐tracked ground‐truth signals (average correlation coefficients 0.9209 and statistically significant p < 0.01). Meanwhile, the experiments also prove their method can achieve high real‐time performance of about 80–160 Hz.

Conclusions:

This method provides a good alternative to traditional external‐landmark‐based tracking methods and may be widely applied for respiratory compensation in ultrasound‐guided liver interventions.
Evaluation of a spectral subtraction strategy to suppress reverberant energy in cochlear implant devices
Authors: Kokkinakis Kostas , Runge Christina , Tahmina Qudsia , Hu Yi
Published: July 2015

The smearing effects of room reverberation can significantly impair the ability of cochlear implant (CI) listeners to understand speech. To ameliorate the effects of reverberation, current dereverberation algorithms focus on recovering the direct sound from the reverberated signal by inverse filtering the reverberation process. This contribution describes and evaluates a spectral subtraction (SS) strategy capable of suppressing late reflections. Late reflections are the most detrimental to speech intelligibility by CI listeners as reverberation increases. By tackling only the late part of reflections, it is shown that users of CI devices can benefit from the proposed strategy even in highly reverberant rooms. The proposed strategy is also compared against an ideal reverberant (binary) masking approach. Speech intelligibility results indicate that the proposed SS solution is able to suppress additive reverberant energy to a degree comparable to that achieved by an ideal binary mask. The added advantage is that the SS strategy proposed in this work can allow for a potentially real-time implementation in clinical CI processors.
Adults, but not children, benefit from a pretrial signal cue in a random-frequency, two-tone masker
Authors: Bonino Angela Yarnell , Leibold Lori J.
Published: July 2015

This study examined the benefit of a pretrial cue, a preview of the signal, on children's (5–10 years) and adults' detection of a 1000-Hz pure-tone signal in a broadband noise or a random-frequency, two-tone masker. No cuing effect was observed with the noise masker, regardless of listener age. In contrast, all but one adult benefited from the cue with the two-tone masker (average = 9.4 dB). Most children showed no cuing effect (average = 0.1 dB) with the two-tone masker. These results suggest that, unlike adults, the provision of a pretrial cue does not promote frequency-selective listening during detection for 5- to 10-year-olds.
Proteotoxic stress reprograms the chromatin landscape of SUMO modification
Authors: Seifert Anne , Schofield Pietà , Barton Geoffrey J. , Hay Ronald T.
Published: July 2015

Cells use SUMO-2 to stabilize chromatin-associated proteins and cope with stress.
Science Signaling
Podcast: 7 July 2015
Authors: Lane-Donovan Courtney , Herz Joachim , VanHook Annalisa M.
Published: July 2015

A secreted protein that controls synaptic plasticity protects neurons from the toxic effects of amyloid β.
B cell receptor signaling dynamics
Authors: Prabakaran Sudhakaran
Published: July 2015

Quantitative mass spectrometry–based proteomics analysis reveals the phosphorylation and ubiquitylation dynamics of B cell receptor complexes.
Clearing out selenoprotein garbage
Authors: Riddihough Guy
Published: July 2015

A surveillance system recognizes and degrades truncated proteins that fail to incorporate a specific amino acid.
Two hits in viral cardiomyopathy
Authors: Frisk Megan
Published: July 2015

Enterovirus-derived C-terminal dystrophin fragment is a dominant-negative peptide representing a new therapeutic target for viral cardiomyopathy remediation.
Kallistatin Ameliorates Influenza Virus Pathogenesis by Inhibition of Kallikrein-Related Peptidase 1-Mediated Cleavage of Viral Hemagglutinin
Authors: Leu Chia-Hsing , Yang Mei-Lin , Chung Nai-Hui , Huang Yen-Jang , Su Yu-Chu , Chen Yi-Cheng , Lin Chia-Cheng , Shieh Gia-Shing , Chang Meng-Ya , Wang Shainn-Wei , Chang Yao , Chao Julie , Chao Lee , Wu Chao-Liang , Shiau Ai-Li
Published: July 2015

Proteolytic cleavage of the hemagglutinin (HA) of influenza virus by host trypsin-like proteases is required for viral infectivity. Some serine proteases are capable of cleaving influenza virus HA, whereas some serine protease inhibitors (serpins) inhibit the HA cleavage in various cell types. Kallikrein-related peptidase 1 (KLK1, also known as tissue kallikrein) is a widely distributed serine protease. Kallistatin, a serpin synthesized mainly in the liver and rapidly secreted into the circulation, forms complexes with KLK1 and inhibits its activity. Here, we investigated the roles of KLK1 and kallistatin in influenza virus infection. We show that the levels of KLK1 increased, whereas those of kallistatin decreased, in the lungs of mice during influenza virus infection. KLK1 cleaved H1, H2, and H3 HA molecules and consequently enhanced viral production. In contrast, kallistatin inhibited KLK1-mediated HA cleavage and reduced viral production. Cells transduced with the kallistatin gene secreted kallistatin extracellularly, which rendered them more resistant to influenza virus infection. Furthermore, lentivirus-mediated kallistatin gene delivery protected mice against lethal influenza virus challenge by reducing the viral load, inflammation, and injury in the lung. Taking the data together, we determined that KLK1 and kallistatin contribute to the pathogenesis of influenza virus by affecting the cleavage of the HA peptide and inflammatory responses. This study provides a proof of principle for the potential therapeutic application of kallistatin or other KLK1 inhibitors for influenza. Since proteolytic activation also enhances the infectivity of some other viruses, kallistatin and other kallikrein inhibitors may be explored as antiviral agents against these viruses.
Determination of Bedaquiline in Human Serum Using Liquid Chromatography-Tandem Mass Spectrometry
Authors: Alffenaar Jan-Willem C. , Bolhuis Mathieu , van Hateren Kai , Sturkenboom Marieke , Akkerman Onno , de Lange Wiel , Greijdanus Ben , van der Werf Tjip , Touw Daan
Published: July 2015

Bedaquiline, a diarylquinoline for the treatment of multidrug-resistant tuberculosis (TB), relies on exposure-dependent killing. As data on drug exposure in specific populations are scarce, pharmacokinetic studies may be of interest. No simple and robust validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method has been reported to date. Therefore, a new method using a quadrupole mass spectrometer was developed for analysis of bedaquiline and
N
-monodesmethyl bedaquiline (M2) in human serum, using deuterated bedaquiline as the internal standard. The calibration curve was linear over a range of 0.05 (lower limit of quantification [LLOQ]) to 6.00 mg/liter for both bedaquiline and M2, with correlation coefficient values of 0.997 and 0.999, respectively. The calculated accuracy ranged from 1.9% to 13.6% for bedaquiline and 2.9% to 8.5% for M2. Within-run precision ranged from 3.0% to 7.2% for bedaquiline and 3.1% to 5.2% for M2, and between-run precision ranged from 0.0% to 4.3% for bedaquiline and 0.0% to 4.6% for M2. Evaluation of serum concentrations in a patient receiving bedaquiline showed high levels at the end of treatment, reflecting accumulation of the drug. More observational pharmacokinetic data are needed to relate altered drug concentrations to clinical outcome or adverse drug effects. A simple LC-MS/MS method to quantify bedaquiline and M2 levels in human serum using a deuterated internal standard has been validated. This method can be used in clinical studies and daily practice.
Population Approach To Analyze the Pharmacokinetics of Free and Total Lopinavir in HIV-Infected Pregnant Women and Consequences for Dose Adjustment
Authors: Fauchet Floris , Treluyer Jean-Marc , Illamola Silvia M. , Pressiat Claire , Lui Gabrielle , Valade Elodie , Mandelbrot Laurent , Lechedanec Jerome , Delmas Sandrine , Blanche Stéphane , Warszawski Josiane , Urien Saik , Tubiana Roland , Hirt Déborah
Published: July 2015

The aims of this study were to describe the unbound and total lopinavir (LPV) pharmacokinetics in pregnant women in order to evaluate if a dosing adjustment is necessary during pregnancy. Lopinavir placental transfer is described, and several genetic covariates were tested to explain its variability. A total of 400 maternal, 79 cord blood, and 48 amniotic fluid samples were collected from 208 women for LPV concentration determinations and pharmacokinetics analysis. Among the maternal LPV concentrations, 79 samples were also used to measure the unbound LPV concentrations. Population pharmacokinetics models were developed by using NONMEM software. Two models were developed to describe (i) unbound and total LPV pharmacokinetics and (ii) LPV placental transfer. The pharmacokinetics was best described by a one-compartment model with first-order absorption and elimination. A pregnancy effect was found on maternal clearance (39% increase), whereas the treatment group (monotherapy versus triple therapy) or the genetic polymorphisms did not explain the pharmacokinetics or placental transfer of LPV. Efficient unbound LPV concentrations in nonpregnant women were similar to those measured during the third trimester of pregnancy. Our study showed a 39% increase of maternal total LPV clearance during pregnancy, whereas unbound LPV concentrations were similar to those simulated in nonpregnant women. The genetic polymorphisms selected did not influence the LPV pharmacokinetics or placental transfer. Thus, we suggest that the LPV dosage should not be increased during pregnancy.
Leishmanicidal Activities of Novel Methylseleno-Imidocarbamates
Authors: Fernández-Rubio Celia , Campbell Daphne , Vacas Andrés , Ibañez Elena , Moreno Esther , Espuelas Socorro , Calvo Alfonso , Palop Juan Antonio , Plano Daniel , Sanmartin Carmen , Nguewa Paul A.
Published: July 2015

The generation of new antileishmanial drugs has become a priority. Selenium and its derivatives stand out as having promising leishmanicidal activity. In fact, some parasites express selenoproteins and metabolize selenium. Recently, selenium derivatives have shown the potential to reduce parasitemia, clinical manifestations, and mortality in parasite-infected mice. In this paper, after selecting four candidates according to drug similarity parameters, we observed that two of them, called compounds 2b [methyl-
N
,
N
′-di(thien-2-ylcarbonyl)-imidoselenocarbamate] and 4b [methyl-
N
,
N
′-di(5-nitrothien-3-ylcarbonyl)-imidoselenocarbamate], exhibit low 50% inhibitory concentrations (IC
50
s) (<3 μM) and good selectivity indexes (SIs) (>5) in
Leishmania major
promastigotes and lack toxicity on macrophages. In addition, in analysis of their therapeutic potential against
L. major
in vitro
infection, both compounds display a dramatic reduction of amastigote burden (∼80%) with sublethal concentrations. Furthermore, in macrophages, these selenocompounds induce nitric oxide production, which has been described to be critical for defense against intracellular pathogens. Compounds 2b and 4b were demonstrated to cause cell cycle arrest in G
1
. Interestingly, evaluation of expression of genes related to proliferation (PCNA), treatment resistance (ABC transporter and alpha-tubulin), and virulence (quinonoid dihydropteridine reductase [QDPR]) showed several alterations in gene expression profiling. All these results prompt us to propose both compounds as candidates to treat leishmanial infections.
Characterization of HIV-1 Resistance to Tenofovir AlafenamideIn Vitro
Authors: Margot Nicolas A. , Johnson Audun , Miller Michael D. , Callebaut Christian
Published: July 2015

Tenofovir alafenamide (TAF) is an investigational prodrug of the HIV-1 nucleotide reverse transcriptase (RT) inhibitor (NtRTI) tenofovir (TFV), with improved potency and drug delivery properties over the current prodrug, tenofovir disoproxil fumarate (TDF). TAF is currently in phase 3 clinical studies for the treatment of HIV-1 infection, in combination with other antiretroviral agents. Phase 1 and 2 studies have shown that TAF was associated with increased peripheral blood mononuclear cell (PBMC) drug loading and increased suppression of HIV-1 replication compared to treatment with TDF. In this study, selection ofin vitroresistance to both TAF and the parent compound, TFV, led to the emergence of HIV-1 with the K65R amino acid substitution in RT with 6.5-fold-reduced susceptibility to TAF. Although TAF is more potent than TFVin vitro, the antiviral susceptibilities to TAF and TFV of a large panel of nucleoside/nucleotide RT inhibitor (NRTI)-resistant mutants were highly correlated (R2= 0.97), indicating that the two compounds have virtually the same resistance profile when assessed as fold change from the wild type. TAF showed full antiviral activity in PBMCs against primary HIV-1 isolates with protease inhibitor, nonnucleoside RT inhibitor (NNRTI), or integrase strand transfer inhibitor resistance but reduced activity against isolates with extensive NRTI resistance amino acid substitutions. However, the increased cell loading of TFV with TAF versus TDF observedin vivosuggests that TAF may retain activity against TDF-resistant mutant viruses.
Protective Effect of Ginsenosides Rg1 and Re on Lipopolysaccharide-Induced Sepsis by Competitive Binding to Toll-Like Receptor 4
Authors: Su Fei , Xue Yin , Wang Yuemin , Zhang Lili , Chen Wangxue , Hu Songhua
Published: July 2015

We previously demonstrated that ginsenosides Rg1 and Re enhanced the immune response in C3H/HeB mice but not in C3H/HeJ mice carrying a mutation in the
Tlr4
gene. The results of the present study showed that both Rg1 and Re inhibited mRNA expression and production of proinflammatory mediators that included tumor necrosis factor α, interleukin-1β, interleukin-6, cyclooxygenase-2, and inducible nitric oxide synthase from lipopolysaccharide (LPS)-stimulated macrophages. Rg1 was found to be distributed both extracellularly and intracellularly but Re was located only extracellularly to compete with LPS for binding to Toll-like receptor 4. Preinjection of Rg1 and Re into rats suppressed LPS-induced increases in body temperature, white blood cell counts, and levels of serum proinflammatory mediators. Preinjection of Rg1 and Re into mice prevented the LPS-induced decreases in total white blood cell counts and neutrophil counts, inhibited excessive expression of multiple proinflammatory mediators, and successfully rescued 100% of the mice from sepsis-associated death. More significantly, when administered after lethal LPS inoculation, Rg1, but not Re, still showed a potent antisepsis effect and protected 90% of the mice from death. The better protection efficacy of Rg1 could result from its intracellular distribution, suggesting that Rg1 may be an ideal antisepsis agent.
In Silico
-Based High-Throughput Screen for Discovery of Novel Combinations for Tuberculosis Treatment
Authors: Singh Ragini , Ramachandran Vasanthi , Shandil Radha , Sharma Sreevalli , Khandelwal Swati , Karmarkar Malancha , Kumar Naveen , Solapure Suresh , Saralaya Ramanatha , Nanduri Robert , Panduga Vijender , Reddy Jitendar , Prabhakar K. R. , Rajagopalan Swaminathan , Rao Narasimha , Narayanan Shridhar , Anandkumar Anand , Balasubramanian V. , Datta Santanu
Published: July 2015

There are currently 18 drug classes for the treatment of tuberculosis, including those in the development pipeline. An
in silico
simulation enabled combing the innumerably large search space to derive multidrug combinations. Through the use of ordinary differential equations (ODE), we constructed an
in silico
kinetic platform in which the major metabolic pathways in
Mycobacterium tuberculosis
and the mechanisms of the antituberculosis drugs were integrated into a virtual proteome. The optimized model was used to evaluate 816 triplets from the set of 18 drugs. The experimentally derived cumulative fractional inhibitory concentration (∑FIC) value was within twofold of the model prediction. Bacterial enumeration revealed that a significant number of combinations that were synergistic for growth inhibition were also synergistic for bactericidal effect. The
in silico
-based screen provided new starting points for testing in a mouse model of tuberculosis, in which two novel triplets and five novel quartets were significantly superior to the reference drug triplet of isoniazid, rifampin, and ethambutol (HRE) or the quartet of HRE plus pyrazinamide (HREZ).
Catalase Expression Is Modulated by Vancomycin and Ciprofloxacin and Influences the Formation of Free Radicals in Staphylococcus aureus Cultures
Authors: Wang Ying , Hougaard Anni B. , Paulander Wilhelm , Skibsted Leif H. , Ingmer Hanne , Andersen Mogens L.
Published: July 2015

Detection of free radicals in biological systems is challenging due to their short half-lives. We have applied electron spin resonance (ESR) spectroscopy combined with spin traps using the probes PBN (
N-tert
-butyl-α-phenylnitrone) and DMPO (5,5-dimethyl-1-pyrroline
N
-oxide) to assess free radical formation in the human pathogen
Staphylococcus aureus
treated with a bactericidal antibiotic, vancomycin or ciprofloxacin. While we were unable to detect ESR signals in bacterial cells, hydroxyl radicals were observed in the supernatant of bacterial cell cultures. Surprisingly, the strongest signal was detected in broth medium without bacterial cells present and it was mitigated by iron chelation or by addition of catalase, which catalyzes the decomposition of hydrogen peroxide to water and oxygen. This suggests that the signal originates from hydroxyl radicals formed by the Fenton reaction, in which iron is oxidized by hydrogen peroxide. Previously, hydroxyl radicals have been proposed to be generated within bacterial cells in response to bactericidal antibiotics. We found that when
S. aureus
was exposed to vancomycin or ciprofloxacin, hydroxyl radical formation in the broth was indeed increased compared to the level seen with untreated bacterial cells. However,
S. aureus
cells express catalase, and the antibiotic-mediated increase in hydroxyl radical formation was correlated with reduced
katA
expression and catalase activity in the presence of either antibiotic. Therefore, our results show that in
S. aureus
, bactericidal antibiotics modulate catalase expression, which in turn influences the formation of free radicals in the surrounding broth medium. If similar regulation is found in other bacterial species, it might explain why bactericidal antibiotics are perceived as inducing formation of free radicals.
Detection of Low-Level Cardinium and Wolbachia Infections in Culicoides
Authors: Mee Peter T. , Weeks Andrew R. , Walker Peter J. , Hoffmann Ary A. , Duchemin Jean-Bernard
Published: July 2015

Bacterial endosymbionts have been identified as potentially useful biological control agents for a range of invertebrate vectors of disease. Previous studies of
Culicoides
(Diptera: Ceratopogonidae) species using conventional PCR assays have provided evidence of
Wolbachia
(1/33) and
Cardinium
(8/33) infections. Here, we screened 20 species of
Culicoides
for
Wolbachia
and
Cardinium
, utilizing a combination of conventional PCR and more sensitive quantitative PCR (qPCR) assays. Low levels of
Cardinium
DNA were detected in females of all but one of the
Culicoides
species screened, and low levels of
Wolbachia
were detected in females of 9 of the 20
Culicoides
species. Sequence analysis based on partial 16S rRNA gene and
gyrB
sequences identified “
Candidatus
Cardinium hertigii” from group C, which has previously been identified in
Culicoides
from Japan, Israel, and the United Kingdom.
Wolbachia
strains detected in this study showed 98 to 99% sequence identity to
Wolbachia
previously detected from
Culicoides
based on the 16S rRNA gene, whereas a strain with a novel
wsp
sequence was identified in
Culicoides
narrabeenensis. Cardinium
isolates grouped to geographical regions independent of the host
Culicoides
species, suggesting possible geographical barriers to
Cardinium
movement. Screening also identified
Asaia
bacteria in
Culicoides
. These findings point to a diversity of low-level endosymbiont infections in
Culicoides
, providing candidates for further characterization and highlighting the widespread occurrence of these endosymbionts in this insect group.